The Doctor enters the TARDIS and prepares to depart, while outside, Rose says goodbye to Jackie and Mickey. As the TARDIS starts up, Rose runs inside and the two travelers smile at each other as the vehicle departs. The Doctor informs her that they're going further than they've ever gone before. The TARDIS arrives in the year 5 billion 23 on New Earth, near the futuristic city of New New York. The Doctor explains how the planet came to exist, unaware that someone is watching them via a mechanical spider drone. In the future, the planet has been built as a homage to Earth after the Sun went supernova. As they talk, a man named Chip watches on the monitors. He realizes that Rose has pure blood, and his mistress, Cassandra, recognizes the girl but says it's impossible that she's there. The Doctor suggests they go to see a nearby hospital and explains that someone in Ward 26 has sent him a plea for help via his psychic paper. As they go, Cassandra insists that Rose's presence is more than coincidence, and she can have her revenge.
The Doctor and Rose arrive at the hospital and Rose is surprised to discover that the nuns that run the place, the Sisters of Plentitude, are humanoid cats. The Doctor gets into an elevator and goes up to Ward 26, and Chip overrides the elevator and sends it up before Rose can enter. She takes another elevator and discovers the disinfectant process. Chip sends her elevator downward. After undergoing full disinfectant, Rose emerges and finds Chip waiting for her. He addresses her by name and offers to take her where she wants to go. She picks up a piece of metal as a weapon and reluctantly follows him.
The Doctor meets with one of the Sisters, Jatt, and notices Frau Clovis tending to her patron, the ailing Duke of Manhattan. She objects to the Doctor's presence, but the Duke of Manhattan informs the Doctor that he's dying of petrified regression. The Doctor warns Jatt that the Duke can't be cured, but she insists that they have to have faith. The Doctor notices a familiar face: the Face of Boe. He asks Jatt to find Rose and then goes to see the Face of Boe. Novice Hame explains that her patient is dying of old age after thousands of years, The Doctor tries to talk to the Face of Boe, but he is unconscious and doesn't respond.
Rose finds herself in a chamber with a projector running footage of a party and an attractive blonde woman. She turns as she realizes Cassandra is behind her, along with Chip, who worships her. Cassandra explains that Chip is a force-grown clone who sees to her physical needs, and notes that Rose had apparently. She explains how her brain survived and she had more skin grown from another part of her body, and that Chip steals medicines to keep her alive. Cassandra insists that she's the only pure human still alive, and points out that the woman on the film is her. She then tells Rose that she's discovered that the Sisters are hiding something, and traps Rose in an electrical field. Chip then activates a device, transferring her mental essence into Rose.
Novice Hame watches over the Face of Boe and talks of how he is the last of his kind, and that legend has it that he has a great secret that he will only speak to one like himself, a lonely wanderer.
Cassandra is less than thrilled with her body at first but is happy to have a younger female body. She informs Chip that Rose is still tucked away inside of her brain, and she can access Rose's memories. Cassandra realizes that the Doctor is with Rose and has a new face, The Doctor calls Rose on her cell phone and Cassandra tries to impersonate Rose's accent. The Doctor doesn't notice, occupied with he is when he sees that the Duke of Manhattan has undergone a complete cure. Matron Casp comes over and claims that they have a simple remedy, but they are unable to reveal it to the Doctor because of patient confidentiality. Casp is called away by Jatt, who tells her that one of their patients is conscious The Matron says that they can't have that.
Cassandra goes to investigate the Sisterhood.
Casp and Jatt go to a hidden chamber with patients inside of storage chambers. They examine one of the patients and are surprised that he is conscious and can speak. He begs them for help but they ignore him and discuss his restored sentience. As they go, Casp tells Jatt to inform the patient and she casually obeys.
Cassandra-in-Rose finds the Doctor, who shows her other patients making miraculous recoveries. He finally notices that she's speaking differently, and Cassandra-n-Rose responds by kissing him. She then walks off, leaving a surprised Doctor. They review the files and find nothing, but Cassandra-in-Rose says she overheard the Sisters discussing Intensive Care. Cassandra-in-Rose gives detailed instructions on how to search the database and the Doctor opens a secret panel. As they go in, Novice Hame notices them enter.
The duo tours the intensive care unit and discovers thousands of storage chambers. The Doctor opens one and finds a man, covered in boils. He apologizes and closes the chamber, and then confirms that the other storage chambers hold similar individuals. The Doctor explains that each one is infected with every disease in the galaxy, and that they're kept sterile... for now. Each one was born sick and the Sisters use them to develop cures for their patients. Novice Hame comes up behind them and explains that the "patients" aren't real people, and the Doctor demands to know how many of them have died over the years. The Sisters were unable to deal with all of the patients that came to them for help, so they grew their own flesh to create cures. The Doctor warns that he won't let it continue, and demands to know what they have done to Rose's brain. Cassandra-in-Rose insists that she's fine, but the Doctor points out that she would care if she saw people dying. Realizing she's been found out, Cassandra-in-Rose explains that she need Rose's body and the Doctor's mind to find out what was going on. She tells him who she really is and that gasses him unconscious. Cassandra-in-Rose then demands to see Matron Casp and sets off an alarm.
Novice Hame warns Jatt and Casp, who tell her to tend to her patients.
The Doctor wakes up in one of the storage chambers and Cassandra-in-Rose tells her that he has three minutes until the scheduled disease-infection program activates. He begs her to let Rose go, and Cassandra-in-Rose says that she will once she finds a better body. Casp and Jatt arrive and ask if they can help, and Cassandra-in-Rose demands money in return for keeping their secret. Matron Casp refuses and warns that they have claws. In response, Cassandra-in-Rose has Chip open the nearby of the storage chambers, including the Doctor's. The infected patients emerge and Cassandra-in-Rose and Chip run off. The Doctor warns the Sisters not to touch them and chases after Cassandra-in-Rose, while the patients advance on the Sisters. One of them jams his hand into the controls, opening the other chambers. The patients advance, touching Matron Casp and killing her in a matter of seconds as diseases spread through her body.
The Doctor tells Cassandra-in-Rose and Chip to go down before they are touched and lethally infected. Meanwhile, Sister Jatt activates quarantine procedures, sealing everyone inside. The patients break into the upper levels, infecting everyone that they touch.
Cassandra-in-Rose leads the Doctor on but Chip is cut off by the patients and the Doctor is forced to leave him. He runs off and hides in a drum of waste product.
Frau Clovis goes to investigate the commotion and seals off the Duke of Manhattan's chamber.
Cassandra-in-Rose realizes that they're trapped in her chamber and the Doctor demands that she release Rose. In response, she releases her mental energy into the Doctor's body. She's impressed with her new body and knows that Rose fancies it from her time in Rose's brain. The patients burst in and Cassandra-in-Doctor panics. Rose has them start climbing.
Novice Hame, Frau Clovis, and the others try to barricade themselves in. Meanwhile, other patients close on Chip, forcing him to hide inside one of the storage chambers.
As they climb up the shaft, Rose tells Cassandra-in-Doctor to leave the Doctor's body so he can come up with a plan, but Cassandra refuses. Sister Jatt climbs up and grabs Rose's leg, trying to get revenge, but another patient touches the sister from below, infecting her and leaving her to plummet down the shaft to her death. Rose and Cassandra-in-Doctor desperately climb upward. They get to a sealed door and Rose directs Cassandra-in-Doctor to use the sonic screwdriver. When she can't she transfers herself back into Rose's body. The Doctor refuses to open it unless she leaves Rose, and Cassandra transfers herself back into the Doctor. However, she realizes there's no escape and Cassandra transfers herself into a pursuing patient long enough for the Doctor to get the door open. Once they' get through the door, Cassandra returns to Rose's body but realizes that the patients have never been touched. Shocked, she follows the Doctor into the Face of Boe's ward and they demonstrate to the others that they're uninfected. Frau Clovis informs them that everyone outside of the room is dead and that she can summon an executive squad. The Doctor warns that if they arrive, they'll break quarantine and destroy the nearby city. Instead, he has everyone assemble the intravenous solutions for every disease and then attaches them to himself. he then jumps into the elevator shaft. Cassandra-in-Rose refuses to go and he suggests she live a little, but she refuses until the patients advance on her. She leaps onto the Doctor and they ride the cable down.
At the bottom of the shaft, the Doctor fills the disinfection system with the intravenous solutions and tells Cassandra-in-Rose to keep a lever pulled, and then jumps down into the car and opens the door to find the patients waiting. He calls them in and they move toward him, and the disinfection system activates automatically. The first ones are exposed and he tells them to touch the others, passing on the cure. He explains to Cassandra-in-Rose that the patients are a new subspecies of human, New Humans, and congratulates her on helping to create them.
Later, the authorities arrive and take away the surviving Sisters. The Doctor goes to see the Face of Boe, who has recovered consciousness. It explains that it had grown tired of the universe until the Doctor had taught it to appreciate life anew. The Face of Boe then says that its secret can wait, and it will tell it to the Doctor when they meet for the third and final time. It then teleports away.
The Doctor then turns to Cassandra-in-Rose and tells her that she's lived long enough, and it's time to die. She asks for his help, but he tells her that everyone dies. Chip arrives and Cassandra-in-Rose decides to take his body since he's a willing volunteer. Before the Doctor can stop her, she transfers into Chip's body. However, she warns that Chip is a half-life and collapses. Cassandra-in-Chip realizes that she's dying and realizes that the Doctor is right. The Doctor has one last thing to do for her. He takes her back in time to the party from the film, the last time that anyone considered Cassandra beautiful. Cassandra-in-Chip thanks the Doctor and he tells her to go to Cassandra. Cassandra-in-Chip approaches her original self and tells her that she's beautiful. Touched and puzzled, Cassandra thanks Cassandra-in-Chip and then calls for help and comforts him as he dies.