The coenzyme nicotinamide adenine dinucleotide (NAD ) has key roles in the regulation of redox status and energy metabolism. NAD depletion is emerging as a major contributor to the pathogenesis of cardiac and renal diseases and NAD repletion strategies have shown therapeutic potential as a means to restore healthy metabolism and physiological function. The pleotropic roles of NAD enable several possible avenues by which repletion of this coenzyme could have therapeutic efficacy. In particular, NAD functions as a co-substrate in deacylation reactions carried out by the sirtuin family of enzymes. These NAD -dependent deacylases control several aspects of metabolism and a wealth of data suggests that boosting sirtuin activity via NAD supplementation might be a promising therapy for cardiac and renal pathologies. This Review summarizes the role of NAD metabolism in the heart and kidney, and highlights the mitochondrial sirtuins as mediators of some of the beneficial effects of NAD -boosting therapies in preclinical animal models. We surmise that modulating the NAD -sirtuin axis is a clinically relevant approach to develop new therapies for cardiac and renal diseases.