A new class of renal cell carcinoma (RCC) is defined by BAP1 loss. BAP1, a nuclear deubiquitinase, is inactivated in 15% of clear-cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells to genotoxic stress. BAP1 and PBRM1 mutations anticorrelate in tumors, and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features. BAP1 and PBRM1 regulate different gene expression programs, and BAP1 loss was associated with high tumor grade. The results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities. BAP1 functions as a two-hit tumor suppressor in RCC, and mutant BAP1 does not act as a dominant negative. BAP1 loss is associated with high-grade tumors and mTORC1 activation. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1 loss is associated with high tumor grade and poor prognosis. BAP1 binds HCF-1 and HCF-1 binding is required for suppression of cell proliferation. BAP1 loss sensitizes renal cancer cells to radiation and PARP inhibitors. BAP1 loss is associated with high-grade tumors. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1 loss is associated with high-grade tumors. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1 loss is associated with high-grade tumors. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1 loss is associated with high-grade tumors. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1 loss is associated with high-grade tumors. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1A new class of renal cell carcinoma (RCC) is defined by BAP1 loss. BAP1, a nuclear deubiquitinase, is inactivated in 15% of clear-cell RCCs. BAP1 cofractionates with and binds to HCF-1 in tumorgrafts. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes RCC cells to genotoxic stress. BAP1 and PBRM1 mutations anticorrelate in tumors, and combined loss of BAP1 and PBRM1 in a few RCCs was associated with rhabdoid features. BAP1 and PBRM1 regulate different gene expression programs, and BAP1 loss was associated with high tumor grade. The results establish the foundation for an integrated pathological and molecular genetic classification of RCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities. BAP1 functions as a two-hit tumor suppressor in RCC, and mutant BAP1 does not act as a dominant negative. BAP1 loss is associated with high-grade tumors and mTORC1 activation. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1 loss is associated with high tumor grade and poor prognosis. BAP1 binds HCF-1 and HCF-1 binding is required for suppression of cell proliferation. BAP1 loss sensitizes renal cancer cells to radiation and PARP inhibitors. BAP1 loss is associated with high-grade tumors. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1 loss is associated with high-grade tumors. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1 loss is associated with high-grade tumors. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1 loss is associated with high-grade tumors. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1 loss is associated with high-grade tumors. BAP1 and PBRM1 mutations anticorrelate in RCC. Tumors with simultaneous inactivation of BAP1 and PBRM1 exhibit rhabdoid features. BAP1