After several decades of research into the macrophage migration inhibitory factor (MIF), its diverse actions in the immune system are yet to be fully revealed. What has become clear is that MIF plays an important role in both innate and adaptive immunity. However, while several pathways mediating the function of MIF in the immune system have been established, its role in pathogenic states such as autoimmune diseases has remained unresolved. MIF has been implicated in different autoimmune diseases, including rheumatoid arthritis, glomerulonephritis, and multiple sclerosis, but knowledge about the underlying cellular and molecular mechanisms is just emerging. However, overall it appears that the inhibition of its proinflammatory action is likely to be a successful new therapeutic strategy for some autoimmune diseases, possibly by reducing the need for steroids. As more aspects of the role of this cytokine in the pathogenesis of autoimmune diseases are elucidated, better strategies to target it therapeutically can be expected.