The von Hippel-Lindau gene (VHL), composed of three exons, encodes a protein, pVHL, with diverse tumor suppressor activities. Germline VHL mutations are found in patients with von HippelLindau (VHL), an autosomal dominant hereditary cancer syndrome in which affected individuals are at risk for the development of highly vascularized benign and malignant tumors including central nervous system hemangioblastomas, retinal hemangiomas, clear cell renal carcinomas (ccRCCs), pheochromocytomas, and pancreatic neuroendocrine tumors (1). Biallelic inactivation of VHL, whether via mutation or promoter methylation, is found in VHL-associated tumors and in nearly 90% of sporadic ccRCC tumors (2,3), the most common form of sporadic kidney cancer. Among its activities, pVHL functions as the substrate recognition module of a multiprotein ubiquitin ligase complex, and, by recruiting hypoxia-inducible factor (HIF) 1α and 2α to this complex, mediates their oxygen-dependent degradation (4). VHL mutations that interfere with HIF-α recognition promote aerobic glycolysis and support neoangiogenesis, perhaps the most intensively studied consequences of pVHL loss. However, regulation of HIF-α expression is unlikely to be the sole mechanism underlying the tumor suppressor function of pVHL. Given its role as the substrate recognition module of a multiprotein complex, it is reasonable to assume that pVHL has additional activities that depend on protein–protein interactions unrelated to (or perhaps complementary with) HIF stabilization, and that deregulation of one or more of these activities contributes to tumor formation, likely in a tissue-specific manner. Indeed, pVHL has been implicated in a number of cellular processes that appear to be HIF independent, including cell cycle regulation, extracellular matrix assembly, and cytoskeleton stability (5). The development of ccRCC is associated with both genetic (eg, VHL germline mutation) and environmental factors, particularly long-term exposure to the industrial solvent trichloroethylene (TCE). Although TCE exposure does not affect the histopathology of sporadic ccRCC, its onset is earlier in TCE-exposed individuals, and the VHL gene in a substantial percentage of these tumors contains a specific mutation of a cytosine to thymidine at nucleo