Genome-wide sequencing studies in human cancer have unmasked a striking frequency of mutations in the genes encoding subunits of the mammalian SWI/SNF (BAF) family of ATP-dependent chromatin remodeling complexes. Our laboratory uses biochemical, structural, and functional genomics-based approaches to study rare, genetically well-defined pediatric cancers including synovial sarcoma, Ewing sarcoma, malignant rhabdoid tumor and others, all of which involve BAF complex perturbations as critical drivers of their oncogenic programs. These studies have informed the mechanistic basis underlying BAF complex targeting and function and have provided new foundations for therapeutic development.