At least three people called David Letterman "an asshole" on this show. Cher was the first: Late Night with David Letterman: Episode dated 22 May 1986 (1986). Shirley MacLaine was the second: Late Night with David Letterman: Episode dated 4 October 1988 (1988). Calvert DeForest, aka Larry 'Bud' Melman, was the third in August 1989.

Letterman left "Late Night" in 1993 for Late Show with David Letterman (1993) on CBS when NBC give the "Tonight Show" to Jay Leno following the departure of Johnny Carson in 1992. However, NBC refused to allow Letterman to use elements that made the show famous such as "Larry 'Bud' Melman" or "The Top Ten List". NBC claimed those bits were their "intellectual property". "The Top Ten List" was renamed "Late Show Top Ten" and "Larry 'Bud' Melman" used his real name, Calvert DeForest.

NBC ordered Letterman to do a short monologue and to not have brass instruments in his band in order to differentiate the show from The Tonight Show Starring Johnny Carson (1962). Letterman later did a longer monologue and had brass instruments on Late Show with David Letterman (1993).

The program's initial weakness was its last remaining link to the talk-show convention: interviews. Letterman struggled with them early on; with some guests he seemed to not care, and others he seemed to try much too hard. The interview improved when the show's comedic vision carried over. Guests were preinterviewed and told they were expected to have a funny story or two to tell.

At age six, Lindsay Lohan appeared as a trick-or-treater dressed as garbage for a Halloween skit ("Things You Find on the Bottom of the D Train").

Bill Murray and Don Herbert were Letterman's very first guests (February 1, 1982).

"Late Night" started building its own repertory company of guests; they weren't the traditional Hollywood stars, but sports figures and news anchors, offbeat comics and sometimes obscure actors. Television names were much more likely to appear than movie names. "Late Night" wasn't about plugging the latest movie; it was about comedy and, mostly, it was about David Letterman.

The program ran four nights a week, Monday to Thursday, from the show's premiere in February 1982 until May 1987 with Friday Night (1983) airing in the 12:30 a.m. slot on Fridays with occasional Late Night specials and reruns. However, Friday shows were added in June 1987 since Friday Night Videos was cut from 90 minutes to 60 minutes.

In September 1991, with The Tonight Show Starring Johnny Carson (1962) being pushed back from 11:30 p.m. to 11:35 p.m., Late Night began starting at 12:35 a.m., at the request of NBC affiliates who wanted more advertising time for their profitable late newscasts.

The first Top Ten List was "Top Ten Words That Almost Rhyme With Peas."

In the months before David Letterman's Late Night show premiered, he had a meeting with David Tebet, an executive from Carson Productions who spelled out the late-night rules: First, no monologue. Second, the band could have no more than four members. Third, the bandleader, or however was going to qualify as Letterman's Ed McMahon, could not sit down at the panel with the host. With those stipulations the show would have Johnny Carson's blessing, but Merrill Markoe couldn't have cared less as she wanted the show to be as different from "Tonight" as possible anyway.

Dave also paid homage to Steve Allen in a series of stunts modeled after Allen's jumps into tubs of Jell-O. In the most memorable one, Letterman wore a Velcro suit and stuck himself to a wall. In another he wore a suit covered in Alka-Seltzer tablets and jumped into a 1,000 gallon tank of water. In a suit of tortilla chips, he jumped in a tank of yogurt dip. He even tried a suit of Rice Krispies so he could snap, crackle, and pop. Each stunt was followed by a slow-motion replay. Other stunts were just goofy, juvenile ideas made hilarious by Letterman's pervasive anarchic attitude.

Letterman displayed his growing verbal virtuosity by calling people on the phone and wringing comedy out of them, or sending remote cameras to places like photo stores and restaurants and starting conversations that somehow presented the mundane as hilarious. Letterman's writers soon discovered that they didn't always have to write material; they could just come up with some goofy premise, drop Dave in the middle of it and watch him fix his brain on it, and turn it into laughs. Merrill Markoe also found strange places for Dave to go for pretaped pieces. They started calling what they were doing "found humor"; it wasn't scripted, it was just Dave finding something funny in whatever situation they placed him in.

Thanks to the reliable laughs he generated, as well as the spontaneity of his interaction with Dave, one comic became the signature "Late Night" guest: Jay Leno. They had been linked from the earliest days together in the comedy clubs. Now they helped each other establish reputations as the two funniest guys with attitudes on television. Jay appeared almost forty times on "Late Night," and the staff almost felt these shows were the best of the season.

The timing of the show's growth coincided with an explosion in sales for videocassette recorders. The A.C. Neilson Company always reported that "Late Night with David Letterman" was among the most taped programs on television.

NBC made the link between this show and The Tonight Show Starring Johnny Carson (1962) closer by giving Carson Productions a weekly fee to cover the cost of making sure the shows didn't duplicate each other in guest bookings. The weekly fee of $5,000 paid the cost of hiring an executive from Carson Productions, David Tebet, a former NBC talent manager who was close to Johnny Carson. Tebet served as liaison between the two shows.

The show would become the place to see talented young comics that "Tonight" simply didn't book such as: Bill Murray, Richard Lewis, Michael Keaton, Sandra Bernhard, and Jeff Altman.

The show would be grounded in the same comic sensibility that Dave and Merrill Markoe brought to The David Letterman Show (1980), only with a bit more organization to it.

Thinking like a broadcaster first and a comic second, Dave found ways to use the fact that they were on television to invent comedy: He took the camera on a behind-the scenes tour on the very first night. Two months later he introduced elevator races in the RCA Building. Later that year they had a real bar mitzvah on the show.

In the search for laughs, Letterman often struck some viewers, and interview subjects, as mean spirited. Cher called him an asshole on the air. He sent Jane Seymour packing, in tears. He went into full interview meltdown with Shirley MacLaine, who refused to do a preinterview, came spoiling for a fight and got one. She said Cher had been right; he said sayonara forever.

Praise arrived before the ratings. Letterman was called refreshing, and later brilliant. "Late Night" was labeled the show of the eighties. Emmy Awards rolled in. Dollars followed. Letterman's audience grew modestly, but steadily, up toward 4 million viewers a night. And those were highly prized viewers: mostly young, mostly male, mostly people who were not reached by other television shows and certainly not in so dense a connection. NBC had built the ideal franchise: two hit shows back to back, while no one else in television had even one entertainment show working in late night.

When Letterman first came to late night, NBC gave advertisers a deal that made them buy some commercials for his show if they wanted to buy into the "Tonight" show. That's how they protected the new entry. By the mid-1980s the positions had reversed. Many advertisers, especially for products, especially for products like beer and running shoes, now wanted to buy into Letterman first. NBC began packaging the two shows to help "Tonight". Advertisers could get a better deal if they bought some "Tonight" commercials in addition to the ones they wanted to buy in "Late Night".