In 2004, Clare started working on her first-published novel, City of Bones, inspired by the urban landscape of Manhattan. City of Bones was released by Simon & Schuster in 2007 and is a contemporary fantasy story revolving around characters Clary Fray, Jace Wayland, and Simon Lewis, which became a The New York Times bestseller upon its release. City of Ashes and City of Glass completed the first trilogy. A subsequent second trilogy contained three more books: City of Fallen Angels, City of Lost Souls, and City of Heavenly Fire.

There is a prequel trilogy called The Infernal Devices, which is set in the same universe as The Mortal Instruments, but set in the Victorian era. This consisting of three books: Clockwork Angel, published on August 31, 2010, Clockwork Prince, published on December 6, 2011, and Clockwork Princess, published on March 19, 2013.

A fourth trilogy set in this universe was announced in 2012, to be collectively known as The Dark Artifices. The new contemporary series is set in Los Angeles, and follow female shadowhunter Emma Carstairs, who was introduced in City of Heavenly Fire. The first book, Lady Midnight, was released in March 2016; the second, Lord of Shadows was released in April 2017; the third, Queen of Air and Darkness was released on December 4, 2018.

As of 2013, Clare resides in Amherst, Massachusetts, with her husband, Joshua Lewis, and three cats.

There are also two series of interconnected short stories set in this universe. The first is The Bane Chronicles, completed in 2014 and written with Sarah Rees Brennan and Maureen Johnson, and the second is the planned Tales from the Shadowhunter Academy, written with Brennan and Johnson as well as Robin Wasserman.

After a disappointing box office performance, subsequent movies in the series were cancelled. A television adaptation of The Mortal Instruments called Shadowhunters: The Mortal Instruments began airing in January 2016. It was canceled after the third season.