The identification and application of the Von Hippel-Lindau (VHL) gene is a seminal breakthrough in kidney cancer research.VHL and its protein pVHL are the root cause of most kidney cancers,and the cascading pathway below them is crucial for understanding hypoxia,in addition to the aforementioned tumorigenesis routes and treatments.We reviewed the history and functions of VHL/pVHL and Hypoxia-inducible factor(HIF),their well-known activities under low-oxygen environments as an E3 ubiquitin ligase and as a tran-scription factor,respectively,as well as their non-canonical functions revealed recently.Additionally,we discussed how their dysregulation promotes tumorigenesis:beginning with chromosome 3 p-arm (3p) loss/epigenetic methylation,followed by two-allele knockout,before the loss of complimentary tumor sup-pressor genes leads cells down predictable oncological paths.These different pathways can ultimately determine the grade,outcome,and severity of the deadliest genitourinary cancer.We finished by investi-gating current and proposed schemes to therapeutically treat clear cell renal cell carcinoma (ccRCC) by manipulating the hypoxic pathway utilizing Vascular Endothelial Growth Factor (VEGF) inhibitors,mammalian target of rapamycin complex 1 (mTORC1) inhibitors,small molecule HIF inhibitors,immune checkpoint blockade therapy,and synthetic lethality.