The ability of NAD(+) to act as a metabolic cofactor and as a rate-limiting cosubstrate for many enzymes, particularly the sirtuins, has led to the identification of a pivotal role of NAD(+) levels in the control of whole-body metabolic homeostasis. Bioavailability and compartmentalization of NAD(+) have become highly relevant issues that we need to understand in order to elucidate how NAD(+) acts both as a readout of the metabolic milieu and as an effector triggering appropriate cellular adaptations.