The series featured Bernie Mac and his wife Wanda raising his sister's three kids: Jordan, Vanessa, and Bryana.

The pilot episode, aired on November 14, 2001, set up the basic premise for the series: the character Bernie Mac takes in his sister's children after she enters rehab (a fictional premise taken from one of Mac's stand-up routines which was eventually featured in the 2000 film, The Original Kings of Comedy).

"In reality, the story is a blend of two real incidents: Mac briefly took in his niece Toya who was an at risk youth and her daughter Monique; a friend of his had to raise her sister's children long-term.

Toward the end of the series, Bryana's long-lost father (Anthony Anderson) returns and drops by occasionally to help Bernie and Wanda with the kids.

Many of his most emotional scenes occurred in segments in which Mac, while still in character, broke the 'fourth wall' and talked to the television audience, which he referred to as "America".

This technique was notably used before an episode during the 2005–2006 season, when Bernie, as himself and wearing a Chicago White Sox cap and jacket, delivered a heartfelt congratulatory message to the baseball organization and its staff on their recent World Series Championship.

Mac, who grew up on Chicago's south-side, was a die-hard fan of the White Sox and was seen at Game 1 of the World Series, in a front row seat.

Mac's character's celebrity worked as a plot device allowing other celebrities to appear on the show as themselves, including Halle Berry, Serena Williams, Chris Rock, Ashton Kutcher, Billy Crystal, Carl Reiner, Don Rickles, Angela Bassett, Ellen DeGeneres, Ice Cube, Isaac Hayes, Flavor Flav, Lucy Lawless, Stone Cold Steve Austin, Triple H, Matt Damon, Charles Barkley, Jon Garland, Jules Sylvester, Sugar Ray Leonard, India Arie, Shaquille O'Neal, Sugar Shane Mosley, Hugh Hefner, Phil McGraw, and Marcus Allen.

The series debuted in its time slot on November 14, 2001, with solid ratings in spite of a weak lead-in, Grounded for Life.

In fall 2002, the series aired against the Damon Wayans comedy My Wife and Kids which may have hurt the show's momentum in the ratings during the first half of its second season run.

In interviews, Wilmore said he was fed up with the network's creative interference with the show, in addition to Fox constantly shuffling it around the schedule.