Prevalence and mortality make cancer a health challenge in need of effective and better tolerated therapeutic approaches, with tumor angiogenesis identified as a promising target for drug development. The epoxygenase products, the epoxyeicosatrienoic acids, are pro-angiogenic, and down-regulation of their biosynthesis by peroxisomal proliferator-activated receptor alpha (PPARalpha) ligands reduces tumor angiogenesis and growth. Endothelial cells lacking a Cyp2c44 epoxygenase, a PPARalpha target, show reduced proliferative and tubulogenic activities that are reversed by the enzyme's metabolites. In a mouse xenograft model of tumorigenesis, disruption of the host Cyp2c44 gene causes marked reductions in tumor volume, mass, and vascularization. The relevance of these studies to human cancer is indicated by the demonstration that: (a) activation of human PPARalpha down-regulates endothelial cell CYP2C9 epoxygenase expression and blunts proliferation and tubulogenesis, (b) in a PPARalpha-humanized mouse model, activation of the receptor inhibits tumor angiogenesis and growth, and (c) the CYP2C9 epoxygenase is expressed in the vasculature of human tumors. The identification of anti-angiogenic/anti-tumorigenic properties of PPARalpha points to a role for the receptor and its epoxygenase regulatory target in the pathophysiology of cancer, and for its ligands as candidates for the development of a new generation of safer and better tolerated anti-cancer drugs.