The opening scene and closing scene of the series share the identical dialogue between two detectives. The first scene of the first episode of the series opens with Detectives Steve Crosetti Jon Polito and Meldrick Lewis Clark Johnson who are walking through a block in Fells Point a waterfront neighborhood in Baltimore city. They are looking for the murder weapon and/or clues for a new murder case. The hour is late. Crosetti tells Lewis that he had just read in a book that stated, "You won't find what you're looking for. It's a mystery. Life is a mystery. Just accept it." Seven years later, in the last scene of the last episode of the series, Detective Rene Sheppard Michael Michele and Meldrick Lewis are searching for clues to a murder in the same part of town. Sheppard tells Lewis that you won't find what you're looking for, life is a mystery, it always will be and you may as well accept it.
One actor has appeared in a recurring role for every television series produced/written by David Simon. Reg E. Cathey appeared in Homicide: Life on the Streets, Homicide: The Movie, The Corner, and The Wire. He also played two characters over a 5 year period on Homicide's "sister" series of, Law & Order: Special Victims Unit,
Several of the cops on the TV show were inspired by the real-life cops in David Simon's 1991 book: (list of Fictional Character/Real Cop) 1. Stan Bolander - Det. Donald Worden 2. Frank Pembleton - Det. Harry Edgerton 3. Tim Bayliss - Det. Tom Pellegrini 4. Det. John Munch - Sgt. Jay Landsman 5. Al Giardello - Lt. Gary D'Addario 6. Det. Rich Garvey - Det. Kay Howard 7. Sgt. Terry McLarney - Det. Steve Crosetti 8. Det. Donald Waltemeyer - Det. Meldrick Lewis. However, the resemblance between the real detectives and their fictional counterparts is not universally viewed as strong. One source said the only thing Pembleton and Edgerton had in common is that they were both African-American cops in Baltimore.
Joe Hansard, who plays gearhead suspect "Jimmy Lee Shields" in the series premiere of Homicide: Life on the Street (1993), also portrayed transient "Nathan Levi Boston" in React Quotes (2008) of David Simon's sister show The Wire (2002). Both episodes of both shows aired after The Superbowl.