Skillfully written and artfully shot, Peirce's evocative first effort was further strengthened by impressive performances by Chloe Sevigny, Peter Sarsgaard, Brendon Sexton III, and a remarkable turn by Hillary Swank as Brandon. The filmmaker heard about the Teena Brandon story while attending Columbia University as a graduate film student and switched her thesis project to this compelling subject from her original similarly themed focus, a spy drama following a woman posing as a man during the Civil War. Fascinated by Brandon's story, Peirce went to Falls City, Nebraska, the town where the drama unfolded, did extensive research and attended the trial of the two men accused of the murders. In 1995, she made a short film on the subject featuring Anna Grace as Brandon; it received an Astrea Production Grant which helped fund the cost of developing the project into a full-length feature. The resulting screenplay (then titled "Take It Like a Man"), co-written by Peirce, was picked up for workshopping at the Filmmaker's Lab of the Sundance Institute in 1997. Upon its release, "Boys Don't Cry" became one of the most talked about and acclaimed independent features of the year, and the fledgling director was applauded for her success in creating a moving but non-sensational modern American tragedy.

Considering herself not unlike Brandon in terms of her drifting nature and search for a comfortable identity, Peirce grew up in various locales within the United States. While attending the University of Chicago, she ran out of money and subsequently moved to Japan to work as an English instructor. She returned to the USA and the university after earning enough money, and also was able to tour Southeast Asia, a trip that yielded photographic work as well as providing creative inspiration. The aspiring filmmaker went on to earn an MFA at Columbia, and made the most of her time at that university, working on numerous short films and forming valuable creative alliances. Peirce made her directorial debut with the 16mm short "The Last Good Breath" (1993), screened to acclaim at various festivals. The following year she was involved in the production of the shorts "Greetings From Africa" and "Miss Ruby's House". Peirce additionally served as an editor on the 16mm animated film "Anastasia and the Queen of Hearts" (1995).