The last decade has witnessed a rapid expansion in our understanding of the mammalian endogenous cannabinoid system. In just a few short years since the discovery of endogenous lipids that serve as cannabinoids in vivo, these molecules have been shown to participate in a broad array of physiological and pathological processes. Consequently, attention has been directed at defining the proteins responsible for endocannabinoid synthesis, transport, and metabolism. Recently, multiple fatty acid oxygenases including, most notably, cyclooxygenase-2 (COX-2), have been implicated in endocannabinoid metabolism. This review will highlight connections between COX-2 and the endogenous cannabinoid system. The available biochemical evidence supporting a role for COX-2 in endocannabinoid metabolism will be presented. Finally, the potential biological consequences of COX-2-mediated endocannabinoid oxygenation will be discussed.