Clear cell renal cell carcinoma (ccRCC) is the most common subtype of RCC and bears a significantly high frequency of hypoxia-inducible factor 2a (HIF-2a) because of von Hippel-Lindau (VHL) tumor suppressor gene mutations. From the first discovery of HIF-2a inhibitors to the promising potency of the HIF-2a inhibitor PT2977 in a clinical Phase II trial for the treatment of advanced RCC, inhibition of HIF-2a has proved to be a novel and effective therapy for RCC. In this review, we briefly discuss the role of HIF-2a in ccRCC and provide insight into recent advances in the discovery, development, and mode of action of HIF-2a allosteric inhibitors.