Kelsey Grammer was born in St. Thomas, U.S. Virgin Islands where his father owned a bar and a small newspaper. When his parents divorced, Grammer and his siblings moved to New Jersey with their mother, but he was primarily raised in Fort Lauderdale, Florida. Grammer's early life was marked by family tragedies: the murder of his father when he was 13, and the untimely deaths of his sister and two half brothers.

Grammer started acting in high school, and in 1973 was accepted into Julliard School of the Arts in New York City. He studied drama for two years before being asked to leave for a lack of focus. After leaving Julliard, Grammer took an internship at the Old Globe Theatre in San Diego, California, where he remained for two years before returning to New York City to pursue a career in theater. Grammer's TV debut was as a cast member of a televised version of Macbeth. Additional TV appearances included Kate & Allie and the mini-series George Washington. In 1984 Grammer landed a recurring role on daytime soap opera Another World. It was during his stint on the soap that he auditioned for the part of Dr. Frasier Crane on Cheers.

Originally conceived as a guest character and love interest for Diane, Frasier Crane became a permanent part of the Cheers cast due to the dynamic between Grammer's uptight psychiatrist and Ted Danson's callow ex-jock Sam Malone, as the men vied for Diane's affections. In 1993, after Cheers was cancelled, Grammer successfully spun-off the character on Frasier, which chronicled Dr. Crane's life after leaving Boston. Grammer garnered 14 Emmy Award nominations (winning 5) and 8 Golden Globe Award nominations (winning twice) for his 20 year portrayal of Dr. Frasier Crane, and he tied the record for the longest continuously running character on television that was previously held by James Arness and Milburn Stone, each of whom portrayed their Gunsmoke characters for 20 years.

Grammer’s talents extend beyond acting. During his run on Frasier, in addition to starring, he sang the theme song, Tossed Salad and Scrambled Eggs, and became the show's executive producer. On the animated series Gary the Rat (2000), Grammer voiced the main character and was executive producer. He executive produces the WB sitcom Girlfriends and NBC's sleeper hit Medium. Grammer is also the voice of Sideshow Bob, Krusty the Clown's forlorn sidekick on The Simpsons, and he was the voice of prospector Stinky Pete in Toy Story 2.

Thrice married, Grammer's personal life has been fodder for the tabloid grist mill. He and his third wife, Camille, have a son and daughter. Grammer also has two daughters from his previous marriages.