Epigenetics as well as post-translational modifications of proteins are emerging as attractive novel targets for anti-cancer therapy. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two classes of enzymes that regulate histone acetylation, and altered activity of these enzymes has been identified in several cancers. An imbalance in histone acetylation can lead to changes in chromatin structure and transcriptional dysregulation of genes that are involved in the control of proliferation, cell-cycle progression, differentiation and/or apoptosis. In addition, several non-histone protein substrates, such as transcription factors, chaperone proteins or tubulin, undergo acetylation as a key post-translational modification that regulates their half-lives and function. Several inhibitors of HDACs have recently been shown to induce growth arrest and apoptosis in a variety of human cancer cells and have been patented as anticancer agents. Although several clinical studies with HDAC inhibitors (HDAC-Is) are ongoing, the molecular basis for their tumor selectivity remains unknown, thereby presenting a challenge for the cancer research community.