Histone deacetylases (HDACs) are one of two counteracting enzyme families whose activity controls the acetylation state of lysine protein residues, notably those contained in the N-terminal extensions of the core histones. Deregulation of the acetylation state of specific lysine residues has been implicated in a multitude of biologic processes, notably cancer, where HDACs are known to be involved in the control of cell cycle progression, cell survival and differentiation. HDAC inhibitors are being developed as anti-neoplastic agents. Nature has led the way in the development of these compounds, with trichostatin A being the first hydroxamic acid HDAC inhibitor identified. Likewise, the disulfide depsipeptide Romidepsin is currently in clinical trials, while an array of cyclic tetrapeptides HDAC inhibitors have been reported. Rational drug design has allowed these cyclic tetrapeptide to be transformed into equally potent small molecule inhibitors selective for either class I or class II HDACs. While acyclic alkyl ketones have been demonstrated to be selective HDAC 1, 2 and 3 inhibitors with efficacy in xenograft models, trifluoromethyl ketones have been shown to be selective inhibitors for class II HDACs and recently have been revealed to bind in the active site of the enzyme in their hydrated form.