Producer Barney Rosenzweig was inspired by his girlfriend Barbara Corday, who recommended Molly Haskell's book From Reverence to Rape, which claimed there had never been a female buddy film; Rosenzweig set out to make one, initially titled Newman & Redford before the title was changed for legal reasons.

No film studio wanted to produce the script, so it was taken to television instead; Rosenzweig stripped out the main plot, keeping only the character development, and pitched it to networks, with only CBS showing interest.

Loretta Swit originated the role of Christine Cagney in the 1981 TV movie but could not continue in the series because the producers of M*A*S*H would not release her from her contract.

Meg Foster played Cagney for the first six episodes in 1982, but CBS replaced her with Sharon Gless because the network felt Foster was too aggressive and might be perceived by viewers as a lesbian.

Sharon Gless was initially unavailable for the role because of her long-term contract with Universal Television, having been the last actress ever signed to such a long-term studio contract in 1972; at the time she was starring in the CBS sitcom House Calls, replacing Lynn Redgrave.

A CBS executive told the press the network canceled the show partly because the female leads seemed 'jarringly tough,' quoted as saying 'We've perceived them as dykes,' a remark that drew widespread protest and fueled a fan letter-writing campaign to save the series.

After the show's second cancellation in 1983, the production sets at Orion had already been destroyed and the cast released from their contracts; actor Tony La Torre had even joined another sitcom, but returned to Cagney & Lacey after that show was canceled just weeks into its run.

Actor Sidney Clute, who played Det. Paul LaGuardia, died of cancer in October 1985 after having completed several episodes of that season; as a tribute, producers kept his name in the opening credits for the remainder of the series.

The first season's theme song 'Ain't That the Way' by Michael Stull, sung by Marie Cain, was replaced the following season by an instrumental theme composed by Bill Conti.

In the sitcom Brooklyn Nine-Nine, Lieutenant Terry Jeffords' twin daughters are named Cagney and Lacey as a nod to the series.