Reversible histone acetylation on lysine residues, regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs), plays an important role in the regulation of gene expression. Aberrant gene expression resulting from increased HDAC activity and histone hypoacetylation has been observed in human tumors and genetic knockdown studies support a role of HDACs in cancer. Treatment with small-molecule inhibitors of HDAC activity results in anti-tumor effects in a variety of transformed cell lines. Several HDAC inhibitors are in clinical development and show anti-tumor activity in cancer patients. Vorinostat (suberoylanilide hydroxamic acid) was the first HDAC inhibitor approved for the treatment of cancer and will be the focus of this article.