Histone deacetylase enzymes, which have been divided into three distinct structural classes, operate by zinc-dependent (class I/II) or NAD-dependent (class III) mechanisms. Class I/II histone deacetylase (HDAC) enzymes are an emerging therapeutic target for the treatment of cancer and other diseases. These enzymes, as part of multiprotein complexes, catalyze the removal of acetyl groups from lysine residues on proteins, including histones. HDAC inhibitors have been shown to bind directly to the HDAC active site and thereby block substrate access, causing a resultant accumulation of acetylated histones. These agents possess diverse biological activities and can affect differentiation, growth arrest, and/or apoptosis in transformed cell cultures. In vivo xenograft studies have further demonstrated many of these agents to be effective in the inhibition of tumor growth. A wide range of structures have been shown to inhibit the activity of class I/II HDAC enzymes, and with few exceptions, these can be divided into structural classes including small-molecule hydroxamates, carboxylates, benzamides, electrophilic ketones, and cyclic peptides. Despite the variety of structural characteristics, all of these HDAC inhibitors can be broadly characterized by a common pharmacophore that includes key elements of inhibitor-enzyme interactions. In addition to the availability of crystal structures, homology models have further aided in the identification and rational design of new HDAC inhibitors for use as chemical tools and potential therapeutics. The high level of interest in developing efficacious HDAC inhibitors and the availability of design tools have led to an expansive group of agents that target class I/II HDACs. This review encompasses the medicinal chemistry and structureactivity relationships (SAR) underlying advances in HDAC class I/II inhibitor discovery, design, and optimization.