Michael J. Fox's final episode contained numerous references to his earlier series, Family Ties (1982), including a cameo appearance by Michael Gross (who played Fox's father in the earlier series), the doctor he plays has a secretary named Mallory, which was Fox's sister's name on the show, a reference to a Republican Senator named "Alex P. Keaton" (Fox's earlier character). Also, Meredith Baxter starred as his mother in earlier episodes, and also was his mother in Family Ties (1982).

Because he suffered from Parkinson's Disease, Michael J. Fox would often hide his left hand in his pocket.

The Mayor (Barry Bostwick) is frequently seen wearing an "I Survived Rocky Horror" pin. Bostwick starred in The Rocky Horror Picture Show (1975) as Brad Majors.

In one episode, Carter (Michael Boatman) and Stewart (Alan Ruck) go to a Rangers game and get a chance to compete in a shot from center contest, Stewart is the only person wearing a Detroit Red Wings jersey, a reference to Alan Ruck's role in Ferris Bueller's Day Off (1986).

The concept for the show was set in motion after the writers had seen Michael J. Fox in The American President (1995), playing one of the President's political aids. They wanted him to play a similar character for television.

Richard Kind (Paul) and Michael Boatman (Carter) are the only actors to appear in every episode of the series.

Tim Allen, Regis Philbin, and David Letterman had cameos. They all voiced Rags the dog. Allen is the more memorable, while one character contemplates jumping out of a window, the dog talks, saying "Do it, and for God's sake, take me with you!"

Carla Gugino originally had second billing as reporter Ashley Schaeffer, carrying on a secret romance with Fox's character during the first season. She was subsequently written out to make Mike unattached, allowing more storylines.

Charlie Sheen's father, Martin, appeared on the show as Charlie Crawford's father, Ray.

Carter was the first non-stereotyped openly gay African-American character to appear regularly on a prime time television series.

The titles of most of the episodes are a play on famous movies.

The first four seasons of the series were filmed in New York City. When Michael J. Fox left the show, and was replaced by Charlie Sheen, production for the remainder of the series moved to Los Angeles.

Charlie Sheen, who played Deputy Mayor Charlie Crawford, and Alan Ruck, who played Chief of Staff Stuart Bondek, made their breakout performances in Ferris Bueller's Day Off (1986).

Mayor Winston's campaign for U.S. Senate, during the fourth season, was inspired by the intended U.S. Senate run in 2000, by New York City Mayor Rudy Giuliani.

Seven of the main cast members also appeared on Scrubs (2001). Michael J. Fox - Dr. Kevin Casey ("My Catalyst" and "My Porcelain God"); Richard Kind - Harvey Corman ("My New Friend", "My Fault", "My Malpractical Decision", and "My Female Trouble"); Barry Bostwick - Mr. Randolph ("My Dirty Secret"); Michael Boatman - Ron Laver ("My Roommates"); Alexander Chaplin (Gaberman) - Sam Thompson ("My Moment of Un-Truth", "My Rite of Passage", "My Scrubs"); Heather Locklear - Julie Keaton ("My First Step" and "My Fruit Cups") and Alan Ruck - Mr. Bragin ("My Lucky Day").

In Young Guns (1988), Emilio Estevez, who is the brother of Charlie Sheen, shoots a man named Charlie Crawford, which is the name of Sheen's character here. Charlie Crawford is shot in one episode of this show.

First in a trio of sitcoms in which Charlie Sheen portrays a character named Charlie. Two and a Half Men (2003) and Anger Management (2012) are the others.

The Mayor's name is "Randall Winston". The Associate Producer's name is also Randall Keenan Winston.

During season one only, at the end of the theme song, when the steam is blowing through the pothole cover, different sounds can be heard in each episode: wailing sirens, the rumbling of a train, a school bell, church bells, barking dogs, hissing cats, et cetera.

Richard Kind played a fictional big city Mayor on Gotham (2014).

Sam Lloyd auditioned for the parts of Stuart and Paul. He later made guest appearances in the second and fifth seasons.

Despite being set in the world of politics, it is never openly stated what political party Mayor Winston is affiliated with. It is difficult to determine as he was seen passing both conservative and liberal legislation throughout the show's run.

The Mayor, Randall Winston, is named for the person that Carter Heywood was based on, associate producer Randall Keenan Winston.

When Betty Ford appeared on the Mary Tyler Moore Show, this was only one of three times a first lady has appeared on a sitcom in the history of television. The next time would be Nancy Reagan on Diff'rent Strokes, and finally Michelle Obama appeared on the sitcom Jesse. Marla Maples, the former wife of future president Trump, would appear on Spin City in the 90s. The only time a president has appeared on a sitcom was when Donald Trump appeared on Suddenly Susan and The Fresh Prince of Bel-Air, in the 90s;( although he was not yet president at this point.) Ironically he co-starred with comedienne and future Trump-hater Kathy Griffin. There has been no sitting president that has appeared on a scripted TV show in the history of television.