Abstract Inactivation of the VHL tumor suppressor gene is the initiating or “truncal” event in both the sporadic as well as hereditary, von Hippel-Lindau (VHL), type of clear cell renal cell carcinomas (ccRCCs) and hemangioblastomas. pVHL forms an ubiquitin ligase complex that targets the HIF (Hypoxia-inducible Factor) transcription factor for proteasomal degradation when oxygen is available. Deregulation of HIF, and particularly HIF2α, drives pVHL-defective tumor formation in vivo. Drugs against the HIF-responsive gene product, VEGF, have been approved for the treatment of ccRCC, but are not curative and have only modest activity against hemangioblastomas. We need new drugs that can, alone or in combination with existing agents, help manage VHL-associated neoplasms. Although our earlier work credentialed HIF2α as a driver in ccRCC, pharmaceutical companies have historically been reluctant to explore transcription factors as drug targets because they are usually considered “undruggable”. Fortunately, structural and pharmacologic studies at UTSW, followed by medicinal chemistry efforts a Peloton Therapeutics, generated the first-in-class HIF2α inhibitor PT-2385 and the related tool compound PT-2399. We and others showed that PT-2399 is active against ccRCC in preclinical models and then co-led a phase 1/2 study of PT-2385 in patients with advanced ccRCC. PT- 2385 was well tolerated and demonstrated early evidence of clinical activity in a subset of heavily pre- treated patients. This work establishes proof of concept that HIF2α can be drugged and highlights the urgent unmet need for the development of novel combination therapeutic strategies and tissue-based predictive biomarkers with which to optimize the clinical use of HIF2α inhibitors. This UO1 brings together four extramural leaders in VHL and ccRCC research, working in close collaboration with W. Marston Linehan, MD, who is the Chief of Urologic Surgery and the Urologic Oncology Branch and Ramaprasad Srinivasan, MD, PhD who is Head of the Molecular Cancer Therapeutics Section, Urologic Oncology Branch, Center for Cancer Research, at the National Cancer Institute (NCI). Dr. Linehan leads the largest clinical program in hereditary kidney cancer and VHL disease in the world and Dr. Srinivasan has directed clinical trials targeting the VHL and other RCC pathways in both sporadic and hereditary forms of RCC. Our team will address key unanswered questions in ccRCC with high clinical impact. First, will combined HIF2α pathway blockade improve clinical outcomes? Second, can tissue-based pharmacodynamic biomarkers explain the therapeutic impact of HIF2α inhibition? Third, does VHL loss create vulnerabilities other than HIF2α that can be targeted? Fourth, what is the impact of HIF2α inhibition on the tumor microenvironment and does this event create therapeutic opportunities?