Using a genetic linkage-based positional cloning approach the VHL gene was identified at chromosome 3p25.5. VHL is mutated in the germlines of affected individuals, and in VHL-associated tumors the mutation is almost always exposed by virtue of chromosomal deletion of the inherited wild-type allele. VHL is also frequently mutated in sporadic, nonpapillary RCC and in familial RCC. This was predicted because such tumors are histologically similar to VHL-associated renal tumors. Knowledge that VHL plays a critical role in sporadic RCC should aid in the future diagnosis and treatment of this malignancy. Detailed analyses of the biology of individual mutations will be required to determine whether the inherited VHL mutations or acquired sporadic mutations cause loss of protein function or have dominant-negative affects. However, the nature of the VHL protein is at present unclear and a complete understanding its function will only be expected after the cloning of the full-length gene.