Von Hippel-Lindau (VHL) disease, a multisystem familial cancer syndrome, is the most common cause of familial renal cell carcinoma. VHL disease is dominantly inherited with variable expression and age-dependent penetrance. The elucidation of the molecular basis for genotype–phenotype correlations in VHL disease will provide a link between specific pVHL functions and tumorigenesis. Interestingly, missense mutations associated with pheochromocytoma retain partial function in some assays, whereas missense mutations which do not cause pheochromocytoma behave as total loss-of-function mutation. Functional studies of the VHL protein have provided insights into a novel mechanism of tumor suppressor gene function and into cellular responses to hypoxia. Further progress in elucidating pVHL function and the relationship between specific functions and tumor susceptibility will provide further insights into the role of pVHL in tumorigenesis and opportunities to develop novel therapies. Effective antiangiogenic therapy may provide a medical approach to the treatment of CNS and retinal hemangioblastomas.