It is becoming clear that the post-translational modification of histone and non-histone proteins by acetylation is part of an important cellular signaling process controling a wide variety of functions in both the nucleus and the cytoplasm. Recent investigations designate this signaling pathway as one of the primary targets of viral proteins after infection. Indeed, specific viral proteins have acquired the capacity to interact with cellular acetyltransferases (HATs) and deacetylases (HDACs) and consequently to disrupt normal acetylation signaling pathways, thereby affecting viral and cellular gene expression. Here we review the targeting of cellular HATs and HDACs by viral proteins and highlight different strategies adopted by viruses to control cellular acetylation signaling and to accomplish their life cycle. BioEssays 25:58–65, 2003. © 2002 Wiley Periodicals, Inc.