This chapter contains three functional parts: an introduction (3.1), a description of several major types of autooxidative mechanisms (3.2–3.4), and a discussion of specific oxidation pathways of drugs with various functional groups and structures in relation to each type of the major autooxidative mechanisms (3.5). In Sections 3.2–3.4, the ubiquitously known Fenton reaction and the little known, but more relevant Udenfriend reaction, are discussed in terms of their roles in free radical-mediated autooxidation by activating molecular oxygen into several reactive oxygen species (ROS), that is, O2−˙/HO2˙, H2O2, and HO˙. The radical ROS then triggers radical chain reactions, in which process organic peroxyl radicals and hydroperoxides are the predominant intermediates. The latter can undergo homolytic cleavage, owing to their relatively low O–O bond dissociation energies, as well as metal ion-catalyzed heterolytic cleavage. The homolytic cleavage generates alkoxyl and hydroxyl radicals, while the heterolytic cleavage reproduces peroxyl radical. Non-radical reactions of peroxides were then discussed, in particular those responsible for the formation of N-oxide, S-oxide, and epoxide degradants. The general mechanism for a less known autooxidative degradation pathway, carbanion/enolate-mediated autooxidation (base-catalyzed autooxidation) is also discussed. This mechanism can be significant for those drug molecules containing somewhat “acidic” carbonated CHn moieties, particularly when the drugs are formulated in liquid form. In Section 3.5, more than 60 examples of drug autooxidation in real life scenarios, that is, oxidation occurring under ambient or various stability conditions, are presented and their underlying degradation mechanisms are discussed in details. These examples cover the functional groups, moieties, and structures that are commonly seen in drug molecules.