NADPH oxidase (NOX) enzymes show great potential as therapeutic pharmacological targets. This Forum revolves around the roles of specific NOX isoforms in oxidative stress-mediated pathologies, available NOX antagonists/agonists as well as the potential side effects of NOX inhibition and the requisite identification of novel oxidative biomarkers as a measure of NOX activity in patients. In addition, an original article reports the discovery of a novel small molecule NOX2 inhibitor. Finally an attractive and innovative therapeutic approach for modulating NOX activity through the inhibition of the proton channel Hv1 is discussed.