[2] She is perhaps best known for creating the 2008 animated feature film Sita Sings the Blues, based on the Ramayana, with parallels to her personal life.

[8] In 1988, Paley moved to Santa Cruz, California, and began to write and draw the strip Nina's Adventures.

In 2002, she wrote and directed Fetch!, a humorous short cartoon feature based on a variety of optical illusions, which has enjoyed popularity ever since.

[12] During this period of this time, Paley also contributed several comic strips for the Voluntary Human Extinction Movement, of which she is a member and occasional spokesperson.

[14] In 2012, Paley posted an animation to Vimeo titled This Land is Mine depicting the Middle East conflicts over history; it was named a Staff Pick.

She expanded it into a feature-length treatment of the Ramayana focused on Rama's wife, Sita, using a variety of animation styles and techniques.

[29] The New York Times review of Sita described it as "ambitious and visually loaded" and the film was named a NYT Critic's Pick.

[30] In 2011 she began work on a project called Seder-Masochism,[6] an animated film about The Exodus, showing the rise of patriarchy and the fall of goddess worship.

[37] Because of obstacles in clearing the rights to Hanshaw's recordings for the Sita Sings the Blues, Paley took active part in the free culture movement.

She wrote and performed the song "Copying Isn't Theft" meant to be freely remixed by other people,[41] with the animated clip issued as Minute Meme #1.

[42] Subtitles for the song were created in 10 other languages and performances in Brazilian Portuguese, French, Italian, and Spanish were published.

[43] Subsequent animations in this series are "All Creative Work Is Derivative",[44] EFF Tribute[45] and "Credit is Due: The Attribution Song".

[47] On 9 March 2010, Paley started publishing on her blog a new three-panel comic strip, Mimi & Eunice, highlighting intellectual property problems and paradoxes.

[51] The website for Sita Sings the Blues includes a wiki where its fans contributed translated subtitles for the DVD of the film.