NAD+ was initially characterized as a coenzyme for oxidoreductases. Though conversions between NAD+, NADH, NADP, and NADPH would not be accompanied by a loss of total coenzyme, it was discovered that NAD+ is also turned over in cells for unknown purposes (Maayan, 1964). In 2000, it became clear that Sir2 and Sir2-related enzymes termed Sirtuins deacetylate lysine residues with consumption of an equivalent of NAD+ and that this activity is required for Sir2 function as a transcriptional silencer (Imai et al., 2000). It was also demonstrated that the Preiss-Handler pathway is required for normal silencing activity in vivo (Smith et al., 2000). NAD+-dependent deacetylation reactions are required not only for alterations in gene expression but also for repression of ribosomal DNA recombination and extension of lifespan in response to calorie restriction (Lin et al. 2000, Lin et al. 2002). NAD+ is consumed by Sir2 to produce a mixture of 2′- and 3′ O-acetylated ADPribose plus nicotinamide and the deacetylated polypeptide (Sauve et al., 2001). Additional enzymes, including poly(ADPribose) polymerases and cADPribose synthases are also NAD+-dependent and produce nicotinamide and ADPribosyl products (Ziegler 2000, Burkle 2001).