The aerobic oxidation of carbon–hydrogen (C–H) bonds in biology is currently known to be accomplished by a limited set of cofactors that largely include heme, nonheme iron, and copper. While manganese cofactors perform difficult oxidation reactions, including water oxidation within Photosystem II, they are generally not known to be used for C–H bond oxidation, and those that do catalyze this important reaction display highly limited intrinsic reactivity. In this seminar, I will describe a handful of homologous enzymes that either require manganese, iron, or mixtures thereof to functionalize strong, aliphatic C–H bonds (BDE = 100 kcal/mol). Structural and spectroscopic studies on these systems reveal redox-active, bimetallic active sites that represent the locus of O2 activation and substrate coordination. Our combined results dramatically expand the known reactivity of biological manganese–containing cofactors, and suggests that many uncharacterized (or mischaracterized) monooxygenases may similarly utilize manganese to perform crucial oxidative biochemical tasks.