Germ line mutations in the VHL tumor-suppressor gene cause von Hippel-Lindau (VHL) disease, a hereditary neoplastic disease associated with clear-cell renal-cell carcinomas (ccRCCs), central nervous system hemangioblastomas and pheochromocytomas. Disruption of VHL, by somatic mutation, hypermethylation of its promoter or chromosomal loss, is also seen in the majority of cases of sporadic ccRCC. The protein product of VHL, pVHL, has multiple functions, the best-documented of which relates to its ability to target hypoxia-inducible factors (HIFs) for polyubiquitination and proteasomal degradation through its role in substrate recognition as part of a ubiquitin ligase complex. Consequently, pVHL-defective ccRCCs overexpress mRNAs that are under the transcriptional control of HIF. Drugs that modulate the downstream targets of the pVHL/HIF pathway, including sunitinib, sorafenib, temsirolimus and bevacizumab, have proven benefit in treating ccRCC. In VHL disease, clear evidence supports strong genotype-phenotype correlations, but the situation in sporadic ccRCC is less clear. Data indicate that VHL alterations have a potential role as prognostic and predictive markers in ccRCC. Future clinical trials should prospectively define the VHL alteration status of study participants so that the true utility of such markers can be determined.