Mitochondria are intracellular organelles that oxidize nutrients, make ATP, and fuel eukaryotic life. Their energy providing function is directly dependent on enzymes and coenzymes contained within the organelle. Perhaps, the most important coenzymes for energy yielding reactions are the pyridine nucleotides NAD(H) and NADP(H). Both aerobic and anaerobic metabolism rely on the electron carrying properties of pyridine nucleotides to regulate energy production. The intracellular NAD+/NADH ratio controls the rate of ATP synthesis by regulating flux through NAD(H)-linked dehydrogenases and by activating NAD+ dependent enzymes that post-translationally modify proteins. Thus, mitochondrial energy transduction pathways can be substantially mediated by NAD+; as an electron carrier exerting control over dehydrogenase enzymes or by activating enzymes that affect protein modification. The importance of this is highlighted in the explosion of recent studies linking impaired NAD+ metabolism to human health and disease. Most notably, studies linking changes in NAD+ availability or altered NAD+/NADH ratio to derangements in metabolic and cellular energy transduction processes. In this review, we focus on the most recent investigative efforts to identify the role NAD+ plays in modulating mitochondrial function and also summarize the current knowledge describing the therapeutic application of elevating NAD+ levels via pharmacologic and genetic approaches to treat human disease.