NADPH oxidases have been discovered as enzymes for the first line host defense. They form reactive oxygen species (ROS), such as superoxide anions or H2O2. Within the last years it became clear, that different NADPH oxidase family members specifically interfere with cellular signaling. The specificity is reached by the mode of activation, the type of ROS produced and the localization of the individual members of the family. Different to all other members of the family, Nox4 is constitutively active and produces directly H2O2. This enables Nox4 to contribute to long term processes rather than acute signaling. The identification of the physiological function of Nox4 was our matter of interest in the last years. We identified the anti-inflammatory potential of Nox4, discovered it’s anti-apoptotic role in endothelial cells as well as it’s impact on cellular differentiation. The talk will highlight some of our main findings, which contribute to the conclusion, that Nox4 is the “good NADPH oxidase”.