When David Letterman left NBC for CBS, the network offered him a three-year, $14 million per year contract, doubling his previous Late Night salary, and CBS's total cost for acquiring the show, including theater renovation, negotiation rights paid to NBC, and staff signings, exceeded $140 million.

CBS purchased the historic Ed Sullivan Theater for $4 million and spent several million more on renovations supervised by architect James Polshek.

NBC claimed intellectual property rights over several Late Night bits, leading to compromises: the 'Viewer Mail' segment became the 'CBS Mailbag', actor Calvert DeForest dropped his character name Larry 'Bud' Melman for his real name, and Paul Shaffer's 'World's Most Dangerous Band' was renamed the 'CBS Orchestra'.

NBC gave Letterman a choice of show titles, either 'Late Show with David Letterman' or 'Nightly with David Letterman', but CBS rejected the latter due to potential confusion with ABC's Nightline and NBC Nightly News.

On the first episode, NBC Nightly News anchor Tom Brokaw joined Letterman on stage in a pre-arranged bit, jokingly confiscating cue cards as 'the intellectual property of NBC,' a nod to the ownership dispute between Letterman and his former network.

During Letterman's opening monologue on the first episode, the orchestra played the theme from The Godfather as he joked about waking up next to the head of a peacock, a reference to NBC's peacock logo.

During his interview on September 7, 1993, Rosie Perez mentioned a party called 'Funkmaster Flex Night,' and Letterman's ignorant response was later sampled by DJ Funkmaster Flex himself, becoming a famous needle drop in hip hop culture; Letterman only learned about this 26 years later when appearing on the Desus and Mero show.

Paul McCartney appeared as a guest on July 15, 2009, in the very theater where the Beatles made their U.S. television debut in 1964, and later performed 'Get Back' on top of the theater's marquee, emulating the Beatles' famous 1969 rooftop concert.

Longtime cue card holder Tony Mendez was fired in 2014 after a long-running dispute with writer Bill Scheft over Scheft micromanaging his job culminated in Mendez physically attacking Scheft.

The show's highest-rated episode aired on February 23, 1994, following the 1994 Winter Olympics figure skating competition, drawing 15 million viewers amid intense public interest in the Nancy Kerrigan/Tonya Harding scandal.

The series finale on May 20, 2015, ran 17 minutes over its scheduled time and drew 13.7 million viewers, making it the highest-rated program across all network television that night, beating every prime time show.