Based on the autobiographical book "The Untouchables" by Eliot Ness and Oscar Fraley, the series dealt with the experiences of Eliot Ness, a United States Federal agent, as he fought crime in Chicago during the 1930s with the help of a special team of agents handpicked for their incorruptibility. This special squad was nicknamed the Untouchables.. The stories often revolved around his enmity with the criminal empire of Chicago mob boss Al Capone and Capone's successor, Frank "the Enforcer" Nitti, and many focused on crimes related to Prohibition. The show starred Robert Stack as Eliot Ness, and was narrated by Walter Winchell. The show drew harsh criticism from some Italian-Americans, who felt it promoted negative stereotypes of them as mobsters and gangsters. Others criticized the show for its high violence content which they felt was having a negative influence on younger viewers.

The series had 118 episodes which ran 50 minutes each. Though the book it was based on chronicled the experiences of Ness and his cohorts over a span of time ranging from 1929 to 1933, some episodes stretched into 1934 and 1935 but the overwhelming majority of episodes were set in the early 1930s (for example, one episode, You Can't Pick the Number, begins with Winchell's words, "October 1932 ... the depths of the Depression"). A few episodes were set primarily in a locale other than Chicago as every now and then Ness and his men would travel to sites such as New York to do battle with the underworld.