The exact contribution of the sirtuin family of NAD+-dependent histone deacetylases to longevity in metazoans is, at present, not completely understood but nonetheless regarded as significant. Despite the rapidly accreting evidence solidifying the role of NAD+-dependent histone deacetylase activity in longevity-promoting experimental interventions, the utility of histone-deacetylase inhibitors in the management of a diverse group of oncologic conditions draws question to the notion of universally beneficial effects of experimental interventions designed to promote deacetylase activity. The recent determination that overexpression of any one of the seven human sirtuin deacetylases fails to extend replicative lifespan in differentiated human cells calls attention to the possibility of unforeseen complexity in the determinants of human lifespan. Furthermore, inhibitors of histone deacetylases have been shown to actually increase lifespan in Drosophila. Delineation of the disparate effects of histone-deacetylase activity in stem cells, progenitor cells, and fully differentiated cells may confirm initial findings suggesting that histone-deacetylase inhibitors push malignant cells towards terminal differentiation, while simultaneously exerting a proliferative and differentiating effect on normal stem cells. This effect may ultimately exert an accelerating influence on the aging of the stem cell population and consequently produce detrimental alterations in stem and progenitor cell populations that compromise organismal-level longevity in mammals, in contrast to findings in Drosophila. This opens the possibility of a new side effect to a widely used chemotherapeutic, as well as the possibility of the generation of novel experimental systems that could leverage the putatively pro-aging influence of histone-deacetylase inhibitors to explore aging.