Protein lysine deacetylases (KDACs), including the classic Zn2+-dependent histone deacetylases (HDACs) and the nicotinamide adenine dinucleotide (NAD+)-requiring sirtuins, are enzymes that play critical roles in numerous biological processes, particularly the epigenetic regulation of global gene expression programs in response to internal and external cues. Dysregulation of KDACs is characteristic of several human diseases, including chronic metabolic, neurodegenerative, and cardiovascular diseases and many cancers. This has led to the development of KDAC modulators, two of which (HDAC inhibitors vorinostat and romidepsin) have been approved for the treatment of cutaneous T cell lymphoma. By their nature, existing KDAC modulators are relatively nonspecific, leading to pan-KDAC changes and undesired side effects. Given that KDACs are regulated at many levels, including transcriptional, post-translational, subcellular localization, and through their complexation with other proteins, it should be possible to affect specific KDAC activity through manipulation of endogenous signaling pathways. In this Minireview, we discuss our present knowledge of the cellular controls of KDAC activity and examples of their pharmacologic regulation.