The family of NADPH oxidases consists of seven members that are all producing reactive oxygen species (ROS). In the cardiovascular systems three NADPH oxidases have been mainly investigated: Nox1, Nox2 and Nox4, which all exhibit different physiological functions such as regulating blood pressure, mediating growth factor signaling and control cell proliferation and differentiation. NADPH oxidases exhibit cell-specific expression patterns and divergent molecular mechanisms controlling activity have been identified for individual Nox proteins. Reactive oxygen species (ROS), specifically generated by individual Nox proteins, act as secondary messengers. ROS- formation by Nox1 and Nox2 is a consequence of an activation of the enzymes by different stimuli such as growth factors, cytokines, and cardiovascular risk factors. An acute ROS- formation has been suggested to result in reversible or irreversible oxidation of thiols in phosphatases leading to a prolonged phosphorylation of several signal transduction molecules. Nox4, in contrast, is constitutively active, and therefore, ROS-formation by this enzyme is controlled on the expression level of the protein. As Nox4 constitutively produces low amounts of ROS this may be of benefit for long lasting processes like differentiation and regulating the expression level of other proteins. These aspects may relate to cellular activation, differentiation, proliferation, angiogenesis and gene expression. In quiescent vessels, NADPH oxidases individually and specifically contribute to signal transduction and to the physiological responses to growth factors and cytokines. Excessive Nox-dependent ROS-formation in vascular disease such as diabetes largely contributes to vascular dysfunction resulting for example in defective angiogenesis and inflammatory activation. Taken together, all present homologues of the NADPH oxidase permit different and specific functions in signal transduction.