The balance between protein acetylation and deacetylation controls several physiological and pathological cellular processes, and the enzymes involved in the maintenance of this equilibrium-acetyltransferases (HATs) and deacetylases (HDACs)-have been widely studied. Presently, the evidences obtained in this field suggest that the dynamic acetylation equilibrium is mostly maintained through the physical and functional interplay between HAT and HDAC activities. This model overcomes the classical vision in which the epigenetic marks of acetylation have only an activating function whereas deacetylation marks have a repressing activity. Given the existence of several players involved in the preservation of this equilibrium, the identification of these complex networks of interacting proteins will likely foster our understanding of how cells regulate intracellular processes and respond to the extracellular environment and will offer the rationale for new therapeutic approaches based on epigenetic drugs in human diseases.