Lysine acetylation is one of the most widely studied post-translational modifications of histones. It plays important roles in the regulation of chromatin remodeling and gene expression. This modification is dynamically regulated in vivo<> by histone acetyltransferases and deacetylases. Besides histone substrates, many histone deacetylases can also catalyze deacetylation of non-histone substrates, and participate in the regulation of various biological pathways. In this review, we discuss the classification, structure, function, and catalytic mechanisms of the four known classes of human histone deacetylases, as well as the progress in the development and application of small molecule inhibitors and activators of these deacetylases.