The most direct link between genetic events that predispose to cancer and activation of the HIF pathway is observed in tumors associated with inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene, particularly VHL-associated clear-cell renal cell carcinoma (CCRCC) (for review see [10]). The gene discussed is VHL; the disease is nonpapillary renal cell carcinoma.