Since the gene structure of macrophage migration inhibitory factor (MIF) was revealed, a broad-spectrum of biological functions of this cytokine have been discovered. The gene structure of MIF is well conserved beyond species, indicating its essential role in cellular functions. Expression of MIF is not limited to immune cells, e.g. T cells and macrophages; this protein is constitutively expressed in a wide variety of cells such as epithelial and endothelial cells. From the data available to date, it is clear that MIF is an anterior pituitary-derived hormone that potentiates lethal endotoxaemia, overrides the glucocorticoid-mediated suppression of inflammatory and immune responses, and plays an essential roles in T cell activation. After cloning rat MIF cDNA, we demonstrated that this protein has a tertiary structure similar to those of 5-carboxymethyl-2-hydroxymuconate isomerase and 4-oxalocrotonate tautomerase, as demonstrated by X-ray crystallography. It was reported that D-dopachrome tautomerase, converting 2-carboxy-2,3-dihydroindole-5,6-quinone (D-dopachrome) into 5,6-dihydroxyindole, was a homologue of MIF in terms of the primary amino acid sequence. Following this, MIF was found to possess isomerase activity, converting D-dopachrome into 5,6-dihydroxyindole-2-carboxylic acid. This finding led to the discovery that the enzymes activity is linked directly to the potentiation of superoxide production by neutrophils. Recently, we isolated the genomic DNA of mouse D-dopachrome. Moreover, we clarified the tertiary protein structure, showing its structural similarity to that of MIF. Bearing this in mind, this review discusses the biological relationship between MIF and D-dopachrome tautomerase.