More than a decade ago people observed that angiogenic responses could be inhibited by antioxidants or enhanced by exogenous reactive oxygen molecules such as hydrogen peroxide. Accumulating experimental evidence suggests that redox modulation of the function of thiol-containing proteins, such as the protein tyrosine phosphatases, by reactive oxygen species has a pivotal role in modulating intracellular signalings. NADPH oxidase is the sole enzymatic system identified so far that has a dedicated function of generating reactive oxygen molecules. It is not surprising that this enzyme has been implicated in modulating angiogenic responses as shown in both in vitro and in vivo studies. NADPH oxidase may exert proangiogenic effects by inducing growth factor release from parenchymal cells and promoting angiogenic activities of vascular endothelial and mural cells. Here we review the redox signaling mechanisms that are involved in modulating angiogenesis, and different NADPH oxidase isoforms that may have a role in such a process. Unlike growth factor receptor-mediated angiogenic signalings, a feature of NADPH oxidase-mediated redox signaling is that, by inhibiting protein tyrosine phosphatases, NADPH oxidase may represent an intracellular signal amplifier for multiple receptor tyrosine kinase-mediated pathways involved in angiogenesis. Pharmacological inhibitors of NADPH oxidase have been used to suppress angiogenesis in different models. Encouragingly, drug targeting of NADPH oxidase has been shown to be effective in reducing pathological angiogenesis such as retinopathy. In summary, NADPH oxidase may be a new drug target for antiangiogenic therapies, yet we are still facing great challenges in achieving specific inhibition of different NADPH oxidase isoforms by drugs.