Recent studies have highlighted the ability of Cu-II to catalyze the aerobic oxidative functionalization of C-H bonds; however, very little is known about the mechanisms of these reactions. Here, we describe the Cu-II-catalyzed C-H methoxylation and amidation of a macrocylic arene substrate with O-2 as the stoichiometric oxidant. Kinetic and in situ spectroscopic studies demonstrate the involvement of three different oxidation states of Cu in the catalytic mechanism, including an aryl-Cu-III intermediate. These observations establish a novel mechanistic pathway that has implications for numerous other Cu-catalyzed aerobic oxidation reactions.