Renal cell carcinoma (RCC) is among the most prevalent malignancies in the USA. Most RCCs are sporadic, but hereditary syndromes associated with RCC account for 2-3 % of cases and include von Hippel-Lindau, hereditary leiomyomatosis, Birt-Hogg-Dube, tuberous sclerosis, hereditary papillary RCC, and familial renal carcinoma. In the past decade, our understanding of the genetic mutations associated with sporadic forms of RCC has increased considerably, with the most common mutations in clear cell RCC seen in the VHL, PBRM1, BAP1, and SETD2 genes. Among these, BAP1 mutations are associated with aggressive disease and decreased survival. Several targeted therapies for advanced RCC have been approved and include sunitinib, sorafenib, pazopanib, axitinib (tyrosine kinase inhibitors (TKIs) with anti-vascular endothelial growth factor (VEGFR) activity), everolimus, and temsirolimus (TKIs that inhibit mTORC1, the downstream part of the PI3K/AKT/mTOR pathway). High-dose interleukin 2 (IL-2) immunotherapy and the combination of bevacizumab plus interferon-α are also approved treatments. At present, there are no predictive genetic markers to direct therapy for RCC, perhaps because the vast majority of trials have been evaluated in unselected patient populations, with advanced metastatic disease. This review will focus on our current understanding of the molecular genetics of RCC, and how this may inform therapeutics.