A century after the identification of a coenzymatic activity for NAD⁺, NAD⁺ metabolism has come into the spotlight again due to the potential therapeutic relevance of a set of enzymes whose activity is tightly regulated by the balance between the oxidized and reduced forms of this metabolite. In fact, the actions of NAD⁺ have been extended from being an oxidoreductase cofactor for single enzymatic activities to acting as substrate for a wide range of proteins. These include NAD⁺-dependent protein deacetylases, poly(ADP-ribose) polymerases, and transcription factors that affect a large array of cellular functions. Through these effects, NAD⁺ provides a direct link between the cellular redox status and the control of signaling and transcriptional events. Of particular interest within the metabolic/endocrine arena are the recent results, which indicate that the regulation of these NAD⁺-dependent pathways may have a major contribution to oxidative metabolism and life span extension. In this review, we will provide an integrated view on: 1) the pathways that control NAD⁺ production and cycling, as well as its cellular compartmentalization; 2) the signaling and transcriptional pathways controlled by NAD⁺; and 3) novel data that show how modulation of NAD⁺-producing and -consuming pathways have a major physiological impact and hold promise for the prevention and treatment of metabolic disease.