My laboratory has a long-standing interest in histone deacetylases (HDACs), enzymes that catalyze the removal of acetyl groups from the lysine residues of histones. The recruitment of HDAC enzymes is a common, although not universal, mechanism by which repressors and co-repressors alter transcription. HDACs are potentially useful targets for anti-cancer therapy because many studies indicate that HDAC inhibitors cause cell cycle arrest, revert cell transformation, and restrain tumor growth in animals. Recent data uncovered novel mechanistic insights about HDACs, which confirm and extend the tremendous value of further developing HDAC inhibitors for cancer treatment. These new findings also help to begin addressing challenges in exploiting HDAC inhibitors to ultimately benefit cancer patients. Additionally, I will discuss recent results that provide us with the potential to develop targeted HDAC therapies for other human diseases.