The reaction specificity of lipoxygenases (ALOX) impacts the biological activity of these enzymes and also constitutes the decisive parameter for enzyme classification. ALOX15 orthologs, commonly known as 12/15-lipoxygenases, have recently been suggested to exhibit mainly arachidonic acid 12-lipoxygenating specificity in mammals ranked in evolution lower than gibbons and 15-lipoxygenating specificity in the higher ranking primates (Adel et al., PNAS 113, E4266–75). This hypothesis was worked out on the basis of the functional characteristics of 15 mammalian ALOX15 orthologs with a focus on three sequence determinants affecting substrate binding in the active site (Triad Concept). This review is aimed at summarizing the currently available functional data on the reaction specificity of mammalian ALOX15 orthologs and at analyzing the primary structures of 97 mammalian ALOX15 isoforms that have been deposited in public sequence databases. Our conclusions suggest that the reaction specificity of ALOX15 orthologs can be predicted by analyzing their amino acid sequence and that 98% of all mammalian ALOX15 orthologs follow the Evolutionary Hypothesis.