The tumor suppressor gene VHL (von Hippel-Lindau tumor suppressor) is located on 3p25.3 and encodes a 30 kDa protein with ubiquitin ligase E3 activity. The protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a critical role in the regulation of gene expression by oxygen. Loss of heterozygosity (LOH) at chromosome 3p and inactivation of the VHL gene by deletion or mutation is the most frequent genetic change in sporadic as well as VHL disease-associated conventional renal cell carcinomas (RCC) whereas alterations of this region are rarely seen in papillary and chromophobe RCC. Recent studies suggest that the determination of the VHL status by FISH can significantly improve the accuracy of kidney tumor biopsy evaluation, providing prognostic information that can guide management decisions.