Inactivation of the von Hippel-Lindau (VHL) tumor suppressor has been linked to a variety of tumors, including clear cell renal carcinoma, retinal and cerebellar hemangioblastoma, and pheochromocytoma. The best documented function of VHL protein (pVHL) relates to its ability to target the hypoxia-inducible transcription factor (HIF) for polyubiquitylation and proteasomal degradation. This chapter focuses on studies published over the past 2 years related to pVHL. These studies include those describing genetically engineered mice that were used to interrogate the relationship between pVHL and HIF in vivo and cell culture studies that underscore the importance of pVHL in epithelial differentiation and maintenance of the primary cilium. In addition, recent work suggests that pVHL regulates neuronal apoptosis in an HIF-independent manner, and this activity is linked to the risk of developing pheochromocytoma.