Crystalline hydrates of hydrolytically susceptible pharmaceuticals are commonly encountered, and are particularly prevalent in the beta-lactam class of antibiotics. In order to rationalize how the apparent chemical incompatibility between water and beta-lactams is reduced through crystallization, a review of the published literature and available structural information on the solid state stability was undertaken. A search in the CSD yielded a total of 32 crystal structures of water-containing beta-lactams which were examined and classified in terms of hydrogen-bonded networks. In most cases the waters of hydration in the single crystal structures were found to fulfill structural roles and were not sufficiently close in proximity to react with the beta-lactam ring. Published data for the solid-state of several hydrates were also considered. In general, the stability data indicate high thermal stability for the crystalline hydrates. Moreover, even when water molecules are in appropriate proximity and orientation with respect to the beta-lactam moiety for a reaction to occur, the crystalline solids remain stable. The use of the crystal structure information along with computational modeling suggests that a combination of proximal relationships, steric and mechanistic arguments can explain the observed solid-state stability of crystalline beta-lactam hydrates.