Rhabdoid and epithelioid sarcomas are aggressive tumors affecting children and young adults. Current treatments are inadequate, chemotherapy-resistant tumors that cannot be surgically removed are near universally lethal. Rhabdoid and epithelioid sarcomas are characterized by inactivation of the SMARCB1 tumor suppressor gene, a key regulator of gene expression. Inactivation of the BAF complex through SMARCB1 loss causes uncontrolled gene expression that requires PRC2 and its protein enzyme EZH2. Based on this idea, we have recently completed the first clinical trial of the EZH2 inhibitor tazemetostat, leading to its FDA approval. However, only a subset of patients received a benefit from this therapy. In two preliminary studies we have identified EZH2-dependent and independent mechanisms of resistance. We have established reliable experimental models to elucidate these molecular mechanisms. We aim to define the link between epigenetic dysregulation and fundamental developmental programs in childhood sarcomas. These studies are expected to lead to new rational targeted epigenetic combination therapies to restore healthy gene expression. We have already identified two combination therapies with synergistic anti-tumor activity in cellular models and will now investigate them in vivo as a prelude to their translation to clinical trials for patients.