The von Hippel-Lindau (VHL) protein is able to suppress tumor growth and to down-regulate many angiogenic factors, and is ubiquitously detected in adult and fetal tissues. This makes VHL an excellent target for therapeutic intervention. Observation of VHL alterations in sporadic tumors has been increasing as a result of examination of abnormalities other than intragenic mutations. These abnormalities include loss of chromosome 3p25, changes in the promoter, down-regulation of transcript, and changes in protein level. This article also presents the finding of differential expression of two common VHL proteins among rat tissues, suggesting tissue- and development-dependent functional difference between these two isoforms. Molecular pathways linking VHL to angiogenesis have been extensively characterized and mechanisms have been proposed to explain how altered VHL leads to tumorigenesis. VHL functions in the presence of oxygen and / or oxygen species. Two strategies are proposed here for anti-tumor and anti-angiogenic treatments of VHL-deficient tumors and those without detectable VHL intragenic mutations. One is to restore wild-type VHL function in VHL-deficient tumors and the other is to enhance wild-type VHL expression and activity in tumors under hypoxic conditions.