The show is the only primetime American drama to feature two Australians (Anthony LaPaglia and Poppy Montgomery) and a Briton (Marianne Jean-Baptiste) all playing Americans in its regular cast.

Without a Trace displayed information about real-life missing persons at the end of most episodes, which led to a kidnapped brother and sister being found on July 25, 2005, and at least five people being located overall thanks to these announcements.

The series takes place within Jerry Bruckheimer's CSI: Crime Scene Investigation universe, culminating in a 2007 crossover where Jack Malone traveled to Las Vegas to help the CSI team while Gil Grissom came to New York to assist the FBI's Missing Persons Unit.

Following a campaign by the conservative group Parents Television Council, CBS was fined a record $3.6 million for indecency over the season 2 episode 'Our Sons and Daughters,' which centered on a teenaged orgy; CBS argued the episode had socially relevant messaging about parental supervision.

Season six's production was interrupted by the 2007–2008 Writers Guild of America strike after only 12 episodes had been completed; the show did not resume filming until the strike ended, returning on April 3, 2008, with six additional episodes.

Without a Trace was the first show to achieve strong ratings against the long-running NBC hit medical drama ER, which, like Without a Trace, was produced by Warner Bros. Television.

The first two showrunners were creator Hank Steinberg and Ed Redlich; Redlich stepped back after season two, with staff writers Jan Nash and Greg Walker taking over, while Steinberg himself left mid-season four to produce The Nine, though he remained an executive producer.

CBS cancelled Without a Trace in 2009 after having to choose between renewing it or Cold Case due to budget cuts; they kept Cold Case instead, only to cancel that series as well at the end of the following season.