Over the past few years, the “epigenetic” regulation of the genome has become increasingly important to understanding both the etiology and fundamental mechanisms of aging and age-related diseases. Key to epigenetic regulation are two classes of lysine-modifying enzymes, the histone deacetylases (sirtuins and HDACs) and the histone acetyltransferases (HATs). Both classes of enzyme are critical for maintaining youthful gene expression patterns, cell cycle progression, DNA repair, stem cells, mitochondria, cell fate, differentiation, cognition, energy utilization, and the pathogenesis of most age-related diseases. Alterations in sirtuin and HDAC function have been linked to neurodegenerative disorders, muscle wasting, cardiac hypertrophy, cancer, HIV infection, and more generally the process of aging. Several HDAC inhibitors have been approved by FDA to treat various cancers. Small molecule modulators of sirtuins are currently in clinical trials for the treatment of cancers, neuromuscular disorders, inflammatory and metabolic disorders. With particular relevance to aging, the sirtuins, a subclass of HDAC, were first identified in yeast genetic studies as regulators of lifespan and the health benefits of dietary restriction. Activation or overexpression of sirtuins have been shown to protect mice and primates from diseases of aging, and extend mean and maximum lifespan of mice. Therefore, a thorough understanding of sirtuins and HDACs is required, not merely for understanding the regulation of chromatin structure, gene regulation and protein function, but also because these enzymes are intimately involved in normal and abnormal cellular processes that greatly impact human health. Although targeting HATs for therapeutic purposes has been relatively slow compared to targeting deacetylases, exciting new progress has also been made in recent years. Importantly, targeting the bromodomains present in many HATs has attracted a lot of attention lately.