Described by the public radio program On Being as "an internet pioneer",[2] Shlain is the co-founder of the Webby Awards and the founder of the International Academy of Digital Arts and Sciences.

[3] In high school, Shlain co-wrote a proposal called Uniting Nations in Telecommunications & Software (UNITAS), which envisioned students all over the world communicating over personal computers and via modems before the advent of the web.

[14] In 2002, Shlain directed, produced and co-wrote Life, Liberty, and the Pursuit of Happiness, a documentary about reproductive rights in America.

[17] Shlain's next documentary, The Tribe,[18] co-written with her husband, Ken Goldberg, explored American Jewish identity through the history of the Barbie doll.

[26] It was selected by the US State Department as a part of the 2013 American Film Showcase and was screened at embassies in the Middle East in November 2013.

[32] The series, which began airing on AOL in 2013 was nominated for an Emmy Award in the News & Documentary for New Approaches: Arts, Lifestyle & Culture in 2014, and has since been viewed more than 40 million times.

[33] Shlain "is often asked to comment about Web culture on television and lectures to groups in the U.S. and internationally", according to the Los Angeles Times,[34] and has spoken at TEDWomen and TEDMED.

[41] In 2019, Shlain's book, 24/6: Giving Up Screens One Day a Week to Get More Time, Creativity, and Connection was published by Simon & Schuster.

[45][46][47][48] In 2022, she exhibited her solo art show Human Nature, including her feminist history dendrochronology (tree ring) piece, Dendrofemonology.

Following her father's death, Shlain and her siblings worked together to edit the manuscript of his final book, Leonardo's Brain: Understanding Da Vinci's Creative Genius.