With Donna remaining in critical condition in a hospital in Germany, Palestinian leaders agree to meet with the U.S. and Israel to discuss a peaceful resolution to the pending conflict. As the three nations meet, Donna's condition worsens, Colin begins to question Josh about his true feelings for Donna.
With bombs falling on terrorist training camps in Syria, Palestine and Israel continue to talk about a resolution to the conflict. Bartlet and Leo continue to clash over the settlement, leaving the two to realize their irreconcilable differences. Meanwhile, Josh returns to Washington and begins questioning Leo's well-being.
The staff returns after the Camp David peace settlement to chaos in the White House after Leo has a heart-attack. With Leo in the hospital, Josh and Toby are assigned to get congressional support for the peace accord. C.J. works to gain additional international support from the U.N. Security Council. Meanwhile, Donna returns home from Germany; and Charlie refuses to take a swimming test that would allow him to graduate.
While Leo continues to recuperate after his heart attack, C.J. is named Chief of Staff. But her first day on the job isn't made easy when an emissary from the Republic of Georgia comes to the White House to offer the U.S. enriched uranium from a former Soviet reactor. Josh goes to the DCCC for tax cut support and meets Matthew Santos, a congressman and potential Presidential candidate from Texas. Meanwhile, Toby and Donna interview applicants to fill C.J.'s old position.
When Josh test drives an SUV and accidentally crashes into a hybrid car, Annabeth Schott, the newly named Press Secretary, must deal with the publicity as well as the general opinion that she's too young for the job. Meanwhile, Zoey throws Charlie a graduation party; Leo gives C.J. hints to succeed as Chief of Staff; and Toby worries that Annabeth may be too young to do well in her new position.
After a U.S. peacekeeping compound is attacked, resulting in several American soldiers being fatally wounded, the White House struggles to contain the story when a soldier speaks out against the mission. Meanwhile, Congressman Santos attaches a patients' bill of rights to a Republican bill, setting up a strategy to add Democratic elements to a Republican agenda; Leo faces off with his nurse; and Charlie starts his job at the White House.
As the staff finalizes President Bartlet's visit to China, their plans are thrown a curve when Bartlet inadvertently accepts a a flag from the Taiwanese delegation representing the Taiwanese Independence Movement. His accidental action leads the Chinese to mobilize their forces, causing chaos among the White House staff.
At a Bartlet family birthday party at the White House, guests Penn and Teller burn an American flag, causing a publicity catastrophe for the staff. With Bartlet's second term nearing its end, candidates for President are emerging, including Senator Arnold Vinick, who has managed to impress Josh. Meanwhile, Bartlet experiences an MS episode while aboard Air Force One; and Josh is asked to run the Vice President's campaign for President.
In China, Bartlet is having difficulty sitting through meetings due to his paralyzing MS episode while aboard Air Force One. Back in Washington, NASA warns the staff that an asteroid is heading towards Earth, leaving Josh and Leo to decide how to prepare for the possible collision. Meanwhile, Donna confronts Josh about her future while Josh continues to search for the perfect Democratic candidate for the upcoming Presidential elections.
The press get wind of a rumor that C.J. is a lesbian, and when C.J. refuses to comment on the rumor, the media becomes increasingly suspicious that the rumors are true. While the rumors fly, a Republican candidate attaches a rider to a bill that would ban gay marriages. Meanwhile, Santos tells Josh he'll run for President -- only if Josh will run his campaign; and Abbey, as well as the staff, assess Bartlet's health.
Santos begins to work on his Presidential campaign and sets up headquarters with Josh in New Hampshire. Together, they sort out a myriad of problems from setting up their office to the ideals and goals of the campaign. Meanwhile, Donna and Will work on Vice President Russell's campaign, but Donna has a hard time accepting that Josh is gone.
Its the day after Bartlet's final State of the Union address, but there's no time to rest with a hostage crisis looming in Bolivia that takes the staff's attention away from an agenda meeting set up by Leo. Meanwhile, as Kate works on the Bolivia situation, C.J. monitors the situation in North Korea; Annabeth tutors Abbey on NASCAR etiquette; and Toby focuses his attention the unemployment situation.
Presidential rivals Santos and Vinick meet by chance at an Iowa motel restaurant after a day of campaigning. Earlier in the day, the two candidates, as well as Vice President Russell spoke at the Iowa Corn Growers' Expo, each having to take a stance on ethanol subsidies. By the end of the day, Santos and Vinick come to realize that they both have worthy opponents.
When the staff learns that the Iranian pilot had mistaken the passenger jet for a U.S. spy plane, Bartlet calls in Lord John Marbury for guidance. Meanwhile, Abbey and C.J. argue over the President's rigorous work schedule; Toby and a law professor help work out a constitution with the representatives of Belarus; and the rest of the staff attempt to avoid an appointment with Miss Universe.
With the New Hampshire primary quickly approaching, Josh has to find a way to get Santos into the local debate between front-runners John Hoynes and Vice President Russell. However, Santos and Josh take a gamble and stage their own debate, bringing in Amy Gardner, Josh’s ex-girlfriend, leading Josh and Santos to clash over the campaign.
Now that Vice President Russell appears to be the Democratic nomination front-runner, Josh is becoming increasingly annoyed that Santos is drawing less press coverage despite his strong New Hampshire finish. Josh begins to suspect that the White House is secretly backing a candidate when he finds a link between Senator Rafferty’s health care plan and Bartlet’s original health care plan. Meanwhile, C.J. deals with lobbyists over a Western drought; and Charlie talks with Kate Harper when a man at his gym asks about her.
When the Speaker of the House won't schedule the President's stem cell bill, Santos hatches a plan to pass the bill. Bartlet reluctantly meets with the economist that he split his Nobel prize with, but the meeting doesn't go well since the two are political rivals. Meanwhile, Toby takes interest in a group of middle school children who come to the White House to talk to the staff about voting age; and Kate deals with a Canadian border crisis.
Super Tuesday is approaching, and Santos flies to Sacramento in order to prepare -- if Santos fails to do well in California, his campaign will be over. While in Sacramento, Santos continues to work to push his health care agenda while he receives pressure from the press to take a stance on California's legislation that would provide driver's licenses to illegal immigrants. Meanwhile, Russell decides not to travel to California; Donna tries to figure out why Hoynes refuses to campaign in California, then takes a bigger role in the Russell campaign by becoming the new spokeswoman.
With rumors flying over the U.S.'s connection to Cuba, Bartlet is forced to decide whether he wants to continue talks with the communist dictator or reaffirm the sanctions that would lead to political fallout. Meanwhile, Leo and Kate find a common connection over corrupted elections and drinking habits.
Vinick wins the Republican nomination for presidency and immediately begins working tirelessly on his campaign. He brings in political operative Bruno Gianelli for advice on choosing a vice presidential candidate and the controversy over Vinick's lack of church going. Meanwhile, the Democrats have a three-way race for the nomination with Russell leading Santos and third-place Hoynes; and Bartlet tries to show party unity.
With Vinick securing the Republican nomination for president, Russell offers Santos the vice president slot in the Democratic ticket -- but Russell has yet to win the Democratic nomination. While Santos and his staff debate the offer, Bartlet gets Leo to help with the nomination stalemate. Meanwhile, the staff is put to work when a space station begins leaking oxygen and a rescue mission becomes more and more complex; and Bartlet catches Charlie leaving Zoey's bedroom at 1 in the morning.
The Democratic convention begins and Santos, Russell and Hoyes continue to hunt for votes. The convention will nominate a candidate, but not before the candidates' scheming catches the attention of the nation. Meanwhile, Bartlet has to decide whether or not to launch a rescue mission to save the astronauts trapped in the space shuttle.