12/15-Lipoxygenase (12/15-LO) catalyzes the oxidation of free and esterified fatty acids thereby generating a whole spectrum of bioactive lipid mediators. This enzyme is involved in the regulation of various homeostatic processes as well as in the pathogenesis of multiple diseases. During the innate and adaptive immune response, 12/15-LO and its products exert both pro- and anti-inflammatory effects. Likewise, this enzyme has been implicated in the pathogenesis of autoimmune disease as well as in the maintenance of self-tolerance. This review will summarize our current knowledge about the role of 12/15-LO and will try to examine the two faces of this enzyme within the context of inflammation and immunity.