A class of metalloenzymes, known as zinc hydrolases, catalyze a variety of hydrolytic reactions on many different substrates in important metabolic pathways. Deacetylation is an example of one of the types of reactions catalyzed by zinc hydrolases. The biological importance of the reactions catalyzed by many zinc hydrolases, including zinc-dependent deacetylases, has made these enzymes pharmaceutical targets for the development of inhibitors and, therefore, a clear understanding of the mechanisms of these enzymes is warranted. This review focuses on the current understanding of the mechanisms catalyzed by various zinc-dependent deacetylases and, in particular, the reaction mechanism catalyzed by the enzyme UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase, also known as LpxC. In general, the zinc-water functions as the nucleophile with zinc stabilization of the tetrahedral intermediate and general-acid-base catalysis (GABC) provided by enzyme residue(s). Two types of GABC mechanisms have been identified, one that uses a single bifunctional GABC and another that uses a GABC pair.