This comprehensive study of 161 primary papillary renal cell carcinomas (PRCCs) using whole-exome sequencing, copy number, mRNA, microRNA, methylation, and proteomic analyses reveals that PRCCs are a heterogeneous disease consisting of two main subtypes: Type 1 and Type 2. Type 1 PRCCs are characterized by *MET* alterations, while Type 2 PRCCs are characterized by *CDKN2A* silencing, *SETD2* mutations, *TFE3* fusions, and increased expression of the NRF2-ARE pathway. A CpG island methylator phenotype (CIMP) was identified in a subset of Type 2 PRCCs, associated with poor survival and *fumarate hydratase (FH)* mutations. The study highlights the distinct molecular and clinical features of Type 1 and Type 2 PRCCs, suggesting that sub-stratification by specific molecular markers may lead to more accurate diagnosis and development of targeted therapies.This comprehensive study of 161 primary papillary renal cell carcinomas (PRCCs) using whole-exome sequencing, copy number, mRNA, microRNA, methylation, and proteomic analyses reveals that PRCCs are a heterogeneous disease consisting of two main subtypes: Type 1 and Type 2. Type 1 PRCCs are characterized by *MET* alterations, while Type 2 PRCCs are characterized by *CDKN2A* silencing, *SETD2* mutations, *TFE3* fusions, and increased expression of the NRF2-ARE pathway. A CpG island methylator phenotype (CIMP) was identified in a subset of Type 2 PRCCs, associated with poor survival and *fumarate hydratase (FH)* mutations. The study highlights the distinct molecular and clinical features of Type 1 and Type 2 PRCCs, suggesting that sub-stratification by specific molecular markers may lead to more accurate diagnosis and development of targeted therapies.