Mutations or aberrations of the von Hippel-Lindau gene are responsible for the hereditary neoplastic syndrome that bears the same name, as well as for the majority of sporadic clear cell renal cell carcinomas. The discovery of this gene and subsequent clarification of its mechanism of action have led to a series of targeted treatments for advanced kidney cancer and have dramatically changed how we manage this disease. The discovery of the VHL gene is a prime example of how discoveries at the bench can inform and revolutionize therapeutics at the bedside. In this review, the authors trace this illuminating tale, from the cloning of the VHL gene, to elucidating its biologic function, to the development of novel therapeutics that have dramatically changed the paradigm of managing advanced renal cell carcinoma. Cancer 2008;113(7 suppl):1768–78. © 2008 American Cancer Society.