In this section, we will summarize and discuss the functions of several E3 ubiquitin ligases, including Von Hippel–Lindau (VHL), hypoxia-associated factor (HAF), as well as deubiquitylases, such as BRCA1-associated protein 1(BAP1), and ubiquitin-specific peptidase 37 (USP37) in the HIF signaling pathway the mechanisms by which their dysregulation leads to RCC. The gene discussed is VHL; the disease is renal cell carcinoma.