Genomic sequencing has revolutionized the understanding of ccRCC by identifying multiple driver genes beyond VHL. Genetically engineered animal models to investigate combinations of VHL, epigenetic, and other genes provide a powerful preclinical model for elucidating the biology of ccRCC, developing novel combinatorial therapies, and identifying candidate biomarkers for clinical validation. Here, VHL is linked to nonpapillary renal cell carcinoma.