Reactive oxygen species (ROS) play important roles in the pathogenesis of cardiovascular disease. Surprisingly, large clinical trials have shown that ROS scavenging by antioxidant vitamins is ineffective or harmful. Therefore, prevention of ROS formation, by targeting specific sources of superoxide anion and other ROS, might prove beneficial. Potential targets include the NADPH oxidases (Nox enzymes), xanthine oxidase, endothelial nitric oxide synthase and mitochondrial oxidases. Nox enzymes play a central role because they can regulate other enzymatic sources of ROS. Statins, angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists block upstream signaling of Nox activation, which contributes to their clinical effectiveness. Here, we discuss novel possibilities where drugs that directly inhibit Nox activation could successfully inhibit oxidative stress.