The discovery of the VHL tumor suppressor loss in ccRCC, and the subsequent overactivity of hypoxia-inducible factor 1-alpha (HIF-1α) transcription factors, facilitated anti-angiogenesis drug development and led to the development of small molecular HIF inhibitors, which are showing tremendous promise in heavily pretreated ccRCC patients [46]. This evidence concerns the gene HIF1A and nonpapillary renal cell carcinoma.