Al Waxman co-starred as Cagney and Lacey's good-natured and sometimes blustery supervisor, Lt. Bert Samuels. Carl Lumbly and Martin Kove played, respectively, fellow detectives Marcus Petrie and Victor Isbecki. Sidney Clute played veteran detective Paul La Guardia. John Karlen co-starred as Mary Beth's husband, Harvey Lacey, and Tony La Torre and Troy Slaten played their sons, Harvey Lacey Jr. and Michael Lacey, respectively. Harvey Atkin played desk sergeant Ronald Coleman. Jason Bernard had the recurring role of Deputy Inspector Marquette during the first two seasons. When the show was brought back in March 1984, Marquette had been replaced by Dep. Inspector Knelman (Michael Fairman), who lasted the duration of the series. In the fourth season, Christine entered into a relationship with Sgt. Dory McKenna (Barry Primus), who battled a drug addiction. After a tumultuous courtship, Christine left him and soon after took up with a more stable suitor, David Keeler (Stephen Macht), a local attorney.

One of the most significant cast changes occurred early in the fifth season, upon the death of Sidney Clute from cancer on October 2, 1985, at the age of 69. Off-screen, Det. LaGuardia had retired from the 14th Precinct and moved to New Jersey with a new female companion less than half his age. Clute had completed filming a few episodes of the 1985–86 season prior to his death. In his honor, the producers kept Clute's name in the opening credits for the rest of the series.

LaGuardia's immediate replacement in the fifth season was Det. Jonah Newman (Dan Shor), a boyish ingenue with an elevated sense of himself. Newman, while popular with the guys, was not above stepping on anyone in order to get the coveted promotion of Detective Second Grade. As a result, Chris and Mary Beth had to force a strained relationship with him at best. Newman developed a crush on Chris but she never knew. Eventually, Newman was partnered with veteran Al Corassa (Paul Mantee), who became a regular midway through season five (Mantee had made three guest appearances in late 1985, in which his character's name was Det. Thomas in the first two episodes, and Corassa in the third) and officially took up the role of experience that LaGuardia had vacated. Their partnership met a sad end in May 1986, when Newman was killed from a random gunshot outside of the local district court, just after receiving his promotion to Second Grade.

The beginning of the sixth season saw the arrival of Manny Esposito (Robert Hegyes), a young, street-savvy detective who became Corassa's new partner. There was quite a clash between the two, as Esposito's freewheeling lifestyle (represented by his casual dress on the job, the desire to make a quick buck, and three ex-wives) put him in contrast with Corassa, the older, more conservative family man with a heightened sense of professionalism. Supporting characters added to the precinct at this time were rookie Officer Tom Basil (Barry Laws) and Officer Beverley Faverty (Beverley Faverty). The following year, Petrie was promoted to sergeant and then departed the 14th Precinct (Carl Lumbly had decided to leave the series). In his place, singer Merry Clayton joined the cast as Verna Dee Jordan, the first new female detective at the precinct since the additions of Cagney and Lacey.