VHL and renal cell carcinoma: As all hereditary VHL-related and up to ~75% of sporadic clear cell RCC (CC-RCC) harbour biallelic von Hippel-Lindau (VHL) gene inactivation, this leads to constitutive activation of hypoxia signaling in tumor cells [Figure 1] with resultant upregulation of angiogenic factors including the vascular endothelial growth factor (VEGF) and platelet derived growth factor.[13, 14] These angiogenic factors, which cause tumors to become highly vascular and thus play a critical role in CC-RCC growth and biology[15] have emerged as treatment targets in patients with mRCC [Figure 2].