The tumorigenesis of clear cell renal cell carcinoma (ccRCC), an aggressive variant of renal cell carcinoma (RCC), is primarily attributable to the mutational inactivation of the Von Hippel–Lindau (VHL) gene. This mutation causes VHL syndrome, which is associated with tumor growth in various body parts, including the brain, spinal cord, eyes, adrenal glands, pancreas, kidney, and reproductive tract. RCC is the leading cause of death in patients with VHL syndrome. The VHL gene acts as a tumor suppressor that prevents the proliferation of various oncogenes by controlling the hypoxia-inducible factor (HIF). The HIF pathway is directly linked to the control of metabolic adaptation, cell proliferation, migration, angiogenesis, and apoptosis, which, in turn, is linked to ccRCC tumorigenesis. Consequently, many treatments have been developed to directly or indirectly inhibit HIF1α. Direct inhibition of HIF-1α was briefly explored but has not yet resulted in any treatment strategy approved by the Food and Drug Administration. Most prevalent are the indirect inhibitors targeting vascular endothelial growth factor receptors (VEGFR), the mammalian target of rapamycin (mTOR), and heat shock protein 90 (Hsp90). The VEGFR inhibitor category has the most FDA-approved drugs as they have been proven to be the most efficacious and safe early on. Thus, VEGFR inhibitors, along with mTOR inhibitors, have become the mainstay in RCC treatment. Most recently, therapies targeting HIF-2α inhibition have gained traction with FDA approval, whereas emerging therapies targeting direct inhibition of hsp90 have shown promise.