The single-electron chemistry of mitochondrial oxidative phosphorylation (ox-phos) by default generates reactive oxygen species (ROS). These ROS have roles in both physiologic cell signaling and numerous pathologic situations. One factor that has the potential to regulate ROS generation is the mild uncoupling of ox-phos, i.e., proton (H(+)) leak across the mitochondrial inner membrane. Proton leak has been shown to decrease ROS generation, whereas ROS have been shown to induce H(+) leak, and this suggests the existence of a feedback loop between ROS and H(+) leak. Interestingly, although H(+) leak is detrimental to ATP synthesis, it has been shown to be cytoprotective in several models of ischemic injury. Herein the molecular basis of both ROS generation and H(+) leak will be reviewed and the consequences of their interaction for mitochondrial function discussed.