In this chapter, various hydrolytic mechanisms are discussed along with a number of factors that have an impact on the rate of hydrolysis, such as temperature, pH, steric hindrance, electronic properties of the substrate, and nature of the leaving group. The discussions are illustrated with approximately 50 examples of drugs containing various functional groups or moieties susceptible to hydrolytic degradation. These functional groups or moieties include ester, lactone, amide, β-lactam, carbamate, phosphates, phosphoramide, sulfonamide, imide, imine, acetal, hemiacetal, ether, and epoxide. The hydrolytic susceptibilities of these drugs are compared, whenever possible, by their hydrolysis activation energies in most cases. In cases where activation energies are not available in the literature, the enthalpy of activation and/or reaction rate constants are used for the comparison. Although such comparisons are of a semi-quantitative nature as the conditions for obtaining these kinetic parameters are not uniformly controlled, one can still get a good sense regarding the relative hydrolytic stability of the drugs discussed.