This study identifies *BAP1* as a novel tumor suppressor gene in clear-cell renal cell carcinoma (ccRCC). Whole-genome and exome sequencing, followed by innovative tumorgraft analyses, identified *BAP1* as a putative two-hit tumor suppressor gene. *BAP1* is a nuclear deubiquitinase that is inactivated in 15% of ccRCCs. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes ccRCC cells *in vitro* to genotoxic stress. Interestingly, *BAP1* and *PBRM1* mutations anticorrelate in tumors, and combined loss of both genes in a few ccRCCs was associated with rhabdoid features. BAP1 and PBRM1 regulate different gene expression programs, and BAP1 loss is associated with high tumor grade. These findings establish the foundation for an integrated pathological and molecular genetic classification of ccRCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.This study identifies *BAP1* as a novel tumor suppressor gene in clear-cell renal cell carcinoma (ccRCC). Whole-genome and exome sequencing, followed by innovative tumorgraft analyses, identified *BAP1* as a putative two-hit tumor suppressor gene. *BAP1* is a nuclear deubiquitinase that is inactivated in 15% of ccRCCs. Mutations disrupting the HCF-1 binding motif impair BAP1-mediated suppression of cell proliferation, but not H2AK119ub1 deubiquitination. BAP1 loss sensitizes ccRCC cells *in vitro* to genotoxic stress. Interestingly, *BAP1* and *PBRM1* mutations anticorrelate in tumors, and combined loss of both genes in a few ccRCCs was associated with rhabdoid features. BAP1 and PBRM1 regulate different gene expression programs, and BAP1 loss is associated with high tumor grade. These findings establish the foundation for an integrated pathological and molecular genetic classification of ccRCC, paving the way for subtype-specific treatments exploiting genetic vulnerabilities.