In recent years, histone deacetylase inhibitors (HDACIs) have been proposed as a budding type of therapeutics with anti-aging effects. Indeed, epigenetic regulatory mechanisms are increasingly appreciated as central to a variety of age-associated processes, and this novel class of drugs targeting epigenetic pathways might be predicted to affect cellular and organismal senescence, genomic instability, and tumorigenesis. This chapter presents an overview of the health-beneficial and life-extending effects of HDACIs, which may be caused by generalized changes in epigenetic regulation of gene expression. Data supporting this hypothesis and other plausible mechanism(s) of HDACIs action are discussed. Overall, findings reviewed in this chapter suggest that uncovering basic genetic mechanisms and metabolic pathways contributing to healthy aging and affected by HDACIs is on the way to the understanding and development of new strategies for treating and preventing age-related human diseases and health span extension.