The research of the last decade highlighted the existence of a family of genes activated by cellular stresses that allow the cells to reactivate defense and repair activities regardless of age. The prolonged activation of these genes enhances the organism health and lifespan. Members of this gene family are called sirtuins (SIRT). The founding member of the SIRT protein family, Sir2 is a limiting component of yeast longevity. Many members of this family have been also identified as key longevity regulators in species ranging from yeast to fly. On the other hand, the role of SIRTs in the regulation of mammalian ageing has been questioned. While SIRTs' effects on lifespan are still a matter of scientific debate, the beneficial effects of SIRTs in terms of physical health and quality of aging are widely accepted. Increasing evidence suggests a pivotal role for SIRTs in mediating the adaptive response to physical exercise. The following review summarizes the knowledge so far acquired on sirtuins' role in mediating beneficial effects of physical exercise. In particular, the first paragraph gives an overture on mammalian sirtuins defining their localization, function when possible, and substrates. In the second paragraph, we discuss recent data regarding alteration of sirtuins expression and activity after physical exercise collected by our laboratory and others'.