Siskind grew up in North Carolina in a house filled with music. Her parents listened to bluegrass and old-time music. By the time she was four-years-old, she was singing and playing piano. She began writing songs at age eleven and finished her first album at fourteen. When she was twenty-one, she moved to Nashville, Tennessee.
Her debut album, Covered (2002), was released independently and included appearances by jazz guitarist Bill Frisell and Jennifer Kimball from the Story, a folk rock duo Kimball formed with Jonatha Brooke. The album's songs were about love, family, and relationships.
Her song "Simple Love" was recorded by Alison Krauss on the album A Hundred Miles or More: A Collection (Rounder, 2007) and received a Grammy Award nomination for Best Female Country Vocal Performance. She toured with Bon Iver, who often finished his concerts with her song "Lovin's for Fools".
Siskind's songs have been recorded by Jeff Austin, Brendan Benson, Madi Diaz, Gabe Dixon, Ari Hest, Wynonna Judd, Claire Lynch, Della Mae, Angaleena Presley, Maia Sharp, Randy Travis, Curtis Wright, and the Infamous Stringdusters.