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IDO2 is a relative of IDO1 implicated in tryptophan catabolism and immune modulation but its specific contributions to normal physiology and pathophysiology are not known. Evolutionary genetic studies suggest that IDO2 has a unique function ancestral to IDO1. In mice, IDO2 gene deletion does not appreciably affect embryonic development or hematopoiesis, but it leads to defects in allergic or autoimmune responses and in the ability of IDO1 to influence the generation of T regulatory cells. Gene expression studies indicate that IDO2 is a basally and more narrowly expressed gene than IDO1 and that IDO2 is uniquely regulated by AhR, which serves as a physiological receptor for the tryptophan catabolite kynurenine. In the established KRN transgenic mouse model of rheumatoid arthritis, where IDO1 gene deletion has no effect, IDO2 deletion selectively blunts responses to autoantigen but has no effect on responses to neoantigen challenge. In human populations, natural variations in IDO2 gene sequence that attenuate enzymatic activity have been reported to influence brain cancer control and adaptive immune responses to the IDO2 protein itself, consistent with the concept that IDO2 is involved in shaping immune tolerance in human beings. Biochemical and pharmacological studies provide further evidence of differences in IDO2 enzymology and function relative to IDO1. We suggest that IDO2 may act in a distinct manner from IDO1 as a set-point for tolerance to "altered-self" antigens along the self-non-self continuum where immune challenges from cancer and autoimmunity may arise.