Specifically, we will discuss the impacts on melanoma aggressiveness and drug resistance of the de-regulation of nicotinamide adenine dinucleotide (NAD) and of its rate-limiting biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) and of the mammalian target of rapamycin (mTOR) pathways, the inhibition of which holds the promise to improve the effectiveness of current first-line treatments for metastatic melanoma. Here, NAMPT is linked to metastatic melanoma.