Oxygen is essential for life growth and development, but hypoxia adaptation is also important in many physiological and pathological processes. At normal oxygen levels, hypoxia-inducible factor 2α (HIF-2α) is ubiquitinated by von Hippel-Lindau (VHL) and then rapidly degraded by the proteasome. Under hypoxia, HIF-2α is not degraded and enters the nucleus to form heterodimers with HIF-β subunit, and then activate target genes’ expression. Renal cell carcinoma (RCC) usually has high-frequency VHL gene inactivation, which leads to the accumulation of HIF-2α and ultimately promotes the initiation and progression of RCC. So, HIF-2α can act as a new therapeutic target in RCC. Although HIF-2α is generally regarded as “undruggable”, the allosteric inhibitors PT2385/PT2977 have been successfully developed, which perform pharmacological effects by specifically antagonizing the formation of HIF-2α/HIF-1β heterodimers. Based on the structure of HIF-2α/HIF-1β heterodimers, an extensive screening of small-molecule libraries was performed and 130 potential HIF-2α inhibitors were generated. After further considering the potency, selectivity and oral viability, PT2385 and PT2977 were chosen, in which PT2385 for in vitro studies and PT2977 for clinical development. PT2977 can selectively inhibit the expression of HIF-2α targeted genes in cultured RCC cells, but do not affect HIF-1α targeted genes. Preclinical and clinical trials have demonstrated that HIF-2α inhibitors are effective in blocking cancer cell growth, proliferation, and tumor regression in RCC. These data also indicated that these inhibitors are more effective and better tolerated and have few side effects than standard drugs in treating RCC. Prolonged HIF-2α inhibitors treatment can also produce drug resistance, which can be partly attributed to key amino acid mutations in binding domain of HIF-2α to inhibitors. These advances mean that HIF-2α allosteric inhibitors are expected to play an important role in the clinical treatment of RCC.