Originally from Harrisburg, PA, Peirce also lived in Miami and Puerto Rico before heading off to college at the University of Chicago. Majoring in English and Japanese literature, Peirce subsequently spent two years in Kobe, Japan, doing photography. Merging her interests in storytelling and images, Peirce returned to the U.S. and enrolled in the graduate film program at Columbia University. While in grad school, Peirce became transfixed by the well-publicized rape and murder of Brandon Teena, a young woman living as a man in Falls City, NE. Peirce headed to Nebraska during the trials of the two men eventually convicted of the brutal crime, and befriended a court reporter who helped Peirce gain access to court documents. Fascinated by Brandon's courage and imagination in re-creating his identity in such a conservative environment, and Lana Tisdel, the woman who loved him, Peirce made the story the subject of her thesis film for Columbia.
After she finished her M.F.A., Peirce approached esteemed independent producer Christine Vachon about transforming her work into a feature. Peirce subsequently spent three years readying the film and searching for an actress to play Brandon, finally casting Brandon candidate Chloe Sevigny as Lana and little-known Beverly Hills, 90210 alum Hilary Swank as Brandon in 1998. All of the preparation, including Peirce's suggestion that Swank live as a boy for several weeks prior to production, paid off when Boys Don't Cry premiered to great acclaim in 1999. Earning raves at film festivals for Swank's career performance and Peirce's sensitive yet unstinting examination of how Brandon lived and died, Boys Don't Cry became a critical and art house success. After Swank and Sevigny racked up critics' prizes, the pair were nominated for Oscars, with Swank taking home the Best Actress statuette. Weathering lawsuits from several of the actual people portrayed, including a skittish Tisdel, Peirce then turned to big studio Hollywood for her next directorial job, an adaptation of Arthur C. Clarke's novel Childhood's End.