VHL and renal cell carcinoma: Indeed, this understanding of VHL biology and the inappropriate pro-angiogenic signaling resulting from VHL inactivation in clear cell RCC has revolutionized the systemic therapy of advanced RCC over the past two decades with the clinical development and eventual regulatory approvals of numerous VEGF receptor tyrosine kinase inhibitors (VEGFR TKIs) including sunitinib, pazopanib, and axitinib.