Sierra attended Cal Poly San Luis Obispo with a major in exercise physiology and spent 10 years working in the fitness industry. She changed careers after attending programming classes at UCLA, later returning to teach a course on "new media interactivity" for UCLA Extension.

She says that her interest in cognitive science was motivated by her epilepsy, a condition for which she takes anti-seizure medication. "My interest in the brain began when I had my first grand mal seizure at the age of four," she wrote on her personal weblog.

She was the lead programmer on the computer games Terratopia, a 1996 children's adventure game released by Virgin Sound & Vision, and All Dogs Go to Heaven, a film-based game released as a free cereal premium by MGM. She also worked as a master trainer for Sun Microsystems, teaching Java instructors how to introduce new Java technologies and developing certification exams. In 1998, she founded the Java programmer's online community JavaRanch.

In March 2007, Sierra abruptly canceled her appearance at the O'Reilly ETech conference in San Diego due to threatening blog posts and emails, including death threats. One blog post included an image of Sierra next to a noose. She wrote: "I have cancelled all speaking engagements. I am afraid to leave my yard, I will never feel the same. I will never be the same."

The harassment increased after the threats were reported in the news: a false account of her career was posted online, along with her address and Social Security number.

The issue triggered public discussion on the concept of a bloggers' code of conduct. Some bloggers, including Robert Scoble, author of the technology blog Scobleizer, temporarily suspended their blogs in a show of support for Sierra. One of the larger issues Scoble felt was highlighted by the incident was online hostility to women: "It's this culture of attacking women that has especially got to stop," Scoble said "[W]henever I post a video of a female technologist there invariably are snide remarks about body parts and other things that simply wouldn't happen if the interviewee were a man."