Lysine ε-amino acetylation has long been recognized as an epigenetically relevant post-translational modification of multiple residues in histone proteins. However, it has become clear that lysine acetylation is not restricted to histones, and therefore, it may be involved in the regulation of a wide variety of proteins, some of which have been identified and studied in detail. More recently, post-translational modifications of lysine side chains by additional acyl groups have also been identified, and some of these appear to be regulated by histone deacetylases (HDACs) and/or sirtuins. In this Concept, new developments are discussed with emphasis on the enzymes that have been shown to catalyze the cleavage of these novel marks, including new assays and inhibitors. Ultimately, a deeper understand of these mechanisms should facilitate the development of ligands with therapeutic potential.