A. Futreal MD Anderson Cancer Center, Houston, TX, USA Insight into the somatic genetics of clear cell renal cell carcinoma (ccRCC) has seen considerable advance in the past few years. Leveraging DNA sequencing approaches we have now begun to elaborate the picture of ccRCC, expanding from that dominated by VHL mutation into a more nuanced and complex view of this disease. Perhaps most striking is the contribution of mutations in the chromatin machinery. We and others have documented recurrent, frequent mutations in histone demethylases/methylases (SETD2, JARID1C, KDM6A) and a major role of chromatin remodeling machinery mutations (PBRM1, BAP1). Further, we have demonstrated marked intra-tumor heterogeneity for this disease, lending further insight into its development. This talk will provide an overview of these key insights and put them into context of a more comprehensive view of ccRCC.