The epigenetic regulation of DNA structure and function is essential for changes in gene expression involved in development, growth, and maintenance of cellular function. Epigenetic changes include histone modifications such as methylation, acetylation, ubiquitination, and phosphorylation. Histone deacetylase (HDAC) proteins have a major role in epigenetic regulation of chromatin structure. HDACs are enzymes that catalyze the removal of acetyl groups from lysine residues within histones, as well as a range of other proteins including transcriptional factors. HDACs are highly conserved proteins divided into two families and based on sequence similarity in four classes. Here we will discuss the roles of Rpd3 in physiology and longevity with emphasis on its role in flies. Rpd3, the Drosophila HDAC1 homologue, is a class I lysine deacetylase and a member of a large family of HDAC proteins. Rpd3 has multiple functions including control of proliferation, development, metabolism, and aging. Pharmacological and dietary HDAC inhibitors have been used as therapeutics in psychiatry, cancer, and neurology.