The series takes place in a seedy bus terminal in St. Louis, Missouri, and originally focused on the somewhat broken people who worked the night shift, and in particular, the lead character's battle with alcoholism.

John Hemingway, recovering alcoholic, has been appointed to the role of night shift manager of the St. Louis bus depot.

Beginning with the second season, Hemingway (and the entire cast) changed from the night shift to the daytime hours, and the alcoholism sub-plot was de-emphasized.

Fellow Night Court actors Harry Anderson, Charles Robinson and Marsha Warfield each appeared in an episode.

Joe Pesci, Richard S. "Kinky" Friedman, Dennis Miller, George Hamilton and Ray Charles also appeared playing themselves in episodes.

Other notable guest appearances included Bobcat Goldthwait, Matthew Perry, Dick Martin, Phil Hartman, Rip Torn, Jane Lynch, Tim Daly, Marion Ross, Donna Mills, Art LaFleur, Joey Lawrence, Molly Shannon, Philip Baker Hall, Len Lesser, Deezer D, Cheryl Tiegs, Dinah Manoff and Mila Kunis.

[81] By Larroquette's own admission, though, the show's first season wasn't prime-time material due to its dark nature[82] – at least not for network television.

Oscar, the old bum who lived in one of the bus station phone booths, was cleaned up and became a shoeshine, and the prostitute character Carly (Gigi Rice) went "straight" – buying the bar and becoming a model citizen.

The producers also gave John a wholesome romantic interest in the form of nurse Catherine Merrick, played by Alison La Placa.

[84] The series was originally to be called Crossroads; however, NBC wished to make the most of John Larroquette's popularity from his previous role on Night Court, and insisted on naming the show after him.

The series' theme song, "The Skrewy St. Louis Blues", is a bluesy tune performed by David Cassidy on acoustic guitar with a scat vocal.