Autoimmune inflammatory diseases occur commonly in developed countries. The treatment of these diseases is usually non-curative and is aimed at suppressing inflammatory end-organ damage. Macrophage migration inhibitory factor (MIF) is a multipotent cytokine that has been implicated in the pathogenesis of numerous autoimmune inflammatory disorders. The selective targeting of MIF with either anti-MIF antibody or specific MIF antagonists may offer new therapeutic avenues for these diseases. Our aim is to discuss MIF-directed therapies as a novel therapeutic approach. The review covers literature from the past 10 years. MIF inhibition has been shown to be efficacious in many experimental and pre-clinical studies of autoimmune inflammatory diseases. The close regulatory relationship between MIF and glucocorticoids makes therapeutic antagonism of MIF a potential steroid-sparing therapy in patients with refractory autoimmune diseases. We expect that MIF antagonism by either small-molecule- or antibody-based approaches will find wide application in the treatment of autoimmune inflammatory diseases. Such therapy also may be informed by the MIF genotype of affected patients.