Atypical teratoid rhabdoid tumor (ATRT) is a rare, highly lethal brain cancer. Most patients are diagnosed as infants or toddlers, and even with aggressive treatment, most patients will not survive more than one year from diagnosis. Given the deadly nature of this tumor and the often-harmful approaches that are required to treat it, there is clearly a need to better understand ATRT biology and translate this into effective treatments. The only recurrent mutations in ATRT result in loss of expression of SMARCB1, a protein that is part of a complex which alters the epigenetic landscape of the cell’s DNA. Using an approach that leverages multiple high-throughput sequencing techniques, patient-derived ATRT cell lines and animal models, we aim to understand how SMARCB1 loss makes ATRT cells more vulnerable to treatment and translate these findings into new therapies for patients. To that end, we recently demonstrated proteins that drive expression of genes necessary for normal cellular development are instead sequestered to genes that contribute to cancer formation in ATRT. We further found that targeting these proteins using drugs currently in clinical use kills tumor cells in ATRT models, highlighting a new approach to treat this cancer in a way that can be rapidly translated to the clinic. By building on these exciting preliminary findings, we will use our results to advance a new way of thinking about ATRT that will help these children survive longer with fewer complications.