Based on the series of Rizzoli & Isles novels by Tess Gerritsen, the plot follows Boston Homicide police detective Jane Rizzoli and Chief Medical Examiner Dr. Maura Isles combining their experiences and strikingly different personalities to solve cases.

Jane and medical examiner Maura Isles investigate a killer with Hoyt's modus operandi plus an interest in necrophilia.

When she wakes up they attempt to kill her, but she manages to disarm them by Tasing them and burning Hoyt's eye with a flare.

Hoyt returns 18 months later through another apprentice, Lola (real name Emily Stern) in "I'm Your Boogie Man".

Having murdered Lola's abusive husband two years earlier, Hoyt uses her Stockholm syndrome, developed over six months in which she was kept in bondage, to his advantage and uses her to stalk Jane.

While speaking to Jane in the prison infirmary, Hoyt tells her to look at what he is reading — Tess Gerritsen's novel, The Silent Girl.

Although she manages to find the bodies of his victims — the family of an old college professor of Hoyt's who was unaware of his expulsion — Hoyt, aided by yet another armed apprentice (a prison guard who was responsible for the stabbing that brought Jane back into his sphere), holds her and Maura hostage in his cell.

Angie Harmon was the first actress cast, taking the title role of police detective Jane Rizzoli.

[9] Sasha Alexander won the role of medical examiner Dr. Maura Isles after auditioning with Harmon.

[24][25] In August 2013, production on the fourth season was suspended when cast member Lee Thompson Young was found dead at his Los Angeles apartment from a self-inflicted gunshot wound.

[26] In the second half of the fifth season, a new character, crime scene analyst Nina Holiday, played by Idara Victor, was introduced.

Series executive producer Jan Nash stated that Nina would not replace Young's character, Frost.

The show has started to air on Calle 13 and Nova in Spain on May 11, 2011[32][33] and was broadcast on Fox Life in Portugal on June 29, 2011.

[30] The series, shown in original broadcast order, began airing on Lifetime in September 2020 as well as Start TV in January 2021.

Rizzoli & Isles was the second most-watched cable program on the evening of July 12, 2010, behind its lead-in, The Closer, which had 110,000 more viewers.

[67] Harmon said that she was not surprised by the attention[68] and that, while it was "super fun" to play a role that has some same-sex romantic vibes, the characters are "straight" and "just best friends".