Discovered in the beginning of the 20(th) century, nicotinamide adenine dinucleotide (NAD(+)) has evolved from a simple oxidoreductase cofactor to being an essential cosubstrate for a wide range of regulatory proteins that include the sirtuin family of NAD(+)-dependent protein deacylases, widely recognized regulators of metabolic function and longevity. Altered NAD(+) metabolism is associated with aging and many pathological conditions, such as metabolic diseases and disorders of the muscular and neuronal systems. Conversely, increased NAD(+) levels have shown to be beneficial in a broad spectrum of diseases. Here, we review the fundamental aspects of NAD(+) biochemistry and metabolism and discuss how boosting NAD(+) content can help ameliorate mitochondrial homeostasis and as such improve healthspan and lifespan.