The study identifies CD74, a Type II transmembrane protein, as the high-affinity receptor for macrophage migration inhibitory factor (MIF). MIF binds to the extracellular domain of CD74, and CD74 is essential for MIF-induced activation of the extracellular signal-regulated kinase-1/2 (ERK-1/2) MAP kinase cascade, cell proliferation, and PGE2 production. Recombinant, soluble CD74 inhibits MIF-mediated ERK-1/2 activation in cell systems. These findings provide a molecular basis for MIF's interaction with target cells and identify CD74 as a natural ligand for MIF, which has implications for immune cell activation and inflammatory diseases.The study identifies CD74, a Type II transmembrane protein, as the high-affinity receptor for macrophage migration inhibitory factor (MIF). MIF binds to the extracellular domain of CD74, and CD74 is essential for MIF-induced activation of the extracellular signal-regulated kinase-1/2 (ERK-1/2) MAP kinase cascade, cell proliferation, and PGE2 production. Recombinant, soluble CD74 inhibits MIF-mediated ERK-1/2 activation in cell systems. These findings provide a molecular basis for MIF's interaction with target cells and identify CD74 as a natural ligand for MIF, which has implications for immune cell activation and inflammatory diseases.