Sirtuins are protein deacetylases/mono-ADP-ribosyltransferases found in organisms ranging from bacteria to humans. This group of enzymes relies on nicotinamide adenine dinucleotide (NAD(+)) as a cofactor linking their activity to the cellular metabolic status. Originally found in yeast, Sir2 was discovered as a silencing factor and has been shown to mediate the effects of calorie restriction on lifespan extension. In mammals seven homologs (SIRT1-7) exist which evolved to have specific biological outcomes depending on the particular cellular context, their interacting proteins, and the genomic loci to where they are actively targeted. Sirtuins biological roles are highlighted in the early lethal phenotypes observed in the deficient murine models. In this chapter, we summarize current concepts on non-metabolic functions for sirtuins, depicting this broad family from yeast to mammals.