The Von Hippel-Lindau (vHL) gene may be altered as a somatic (acquired) alteration and/or as a germline alteration associated with a rare autosomal dominant inherited cancer syndrome predisposing to a variety of malignant and benign tumors including clear cell renal cell carcinoma (ccRCC). The protein encoded by this gene is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. Biallelic VHL gene defects (truncation and missense) occur in approximately 75% of ccRCC cases. In addition, approximately 19% of tumors show evidence of inactivation by methylation of the VHL gene promoter. Studies of VHL mutational status as a prognostic marker in advanced sporadic RCC have been inconsistent. However, recent studies with VEGF-inhibitors suggested that loss of function mutations in VHL were associated with treatment response. There are ongoing clinical trials using the current VEGF-tyrosine kinase inhibitors specifically in patients with vHL. Correlation with clinical findings and genetic counseling may be helpful if there is clinical concern for an inherited cancer syndrome. Germline variants are not reported as part of the analysis for the whole exome sequencing assay for tumors.