Backgrounds: Obesity is a major risk factor for cardiovascular disease, diabetes, and cancer, which are all closely linked to angiogenesis. Resistin, originally discovered as a novel adipokine, has been shown to be increased in obese individuals. However, the effects of resistin on endothelial cells and angiogenesis are virtually unknown. Here, we investigated the effects of resistin on angiogenesis and putative signaling pathways in endothelial cells. Methods: To evaluate in vitro angiogenesis we measured Human umbilical endothelial cell (HUVEC) proliferation, migration, and matrigel tube formation with human recombinant resistin concentration of 10ng/ml and 50ng/ml. In vivo, we implanted matrigel plug with control buffer or resistin 50ng/ml at abdomen of C57BL mouse subcutaneously with or without inhibitors. After 1wk we harvested matrigel plugs, made paraffin sections and evaluated them histologically. To evaluate cell signaling we used Western blot analysis. Results: Human recombinant resistin (50ng/ml) increased HUVEC proliferation and migration. This augmentation of EC proliferation and migration by resistin, led to significant increase of capillary tube formation. Furthermore, we confirmed in vivo, using a matrigel plug assay, that angiogenesis was significantly enhanced by human recombinant resistin. Western blot analysis showed that resistin increases the phosphorylation, and thus, the activation of mainly Akt and to a lesser degree, Erk1/2, two well known pro-proliferating signaling molecules. Increased Capillary formation with resistin significantly reversed by mainly LY294002, a PI3-kinase inhibitor, and to a lesser degree, by PD98059, a MEK inhibitor. LY294002 also significantly reversed the increased migratory effects of resistin, suggesting these effects were mediated by PI3-kinase/Akt pathways. Conclusions: These data demonstrates resistin enhances EC proliferation, migration, and increased capillary formation, thus enhancing angiogenesis mainly through PI3-kinase/Akt pathway and partially through MEK pathway. Our findings suggest that resistin may play a significant role in cardiovascular disease or cancer regarding angiogenesis in obese patients.