NAD(+) is a central metabolite in the cell. Changes in NAD(+) abundance and the activity of NAD(+)-dependent enzymes, such as the sirtuins, are at the core of metabolic/mitochondrial diseases, such as obesity and diabetes, and of cancer and neurodegeneration. Here, we discuss how maintaining or raising NAD(+) levels can improve metabolism and prevent age-related functional decline and associated disease, and how basic scientific discoveries in the NAD(+) signaling pathway are being translated to the clinic.