Macrophage migration inhibitory factor (MIF) describes one of the first cytokine activities to be discovered, but the precise role of this immunologic mediator in the host response only now is being understood. MIF is produced constitutively by diverse cell types, and it circulates normally in the blood at low but immunoregulatory concentrations. Diverse pro-inflammatory or invasive stimuli lead to a rapid upregulation in the release of MIF from pre-formed stores in monocytes/macrophages and other cell types. MIF is necessary for the optimal production of TNF and IL-1, and it upregulates the expression of innate receptors such as TLR-4 and a number of secondary effectors important for innate immunity. Once secreted, MIF has a unique role in inhibiting the activation-induced, p53-dependent apoptosis of monocytes/ macrophages, which is a response that serves to spatially and temporally limit monocyte/macrophage activation responses. This action of MIF results in a necessary but, in certain circumstances, pathologically excessive proinflammatory response. MIF also induces a sustained pattern of ERK-1/2 MAP kinase activation, and it regulates Jab1- mediated transcriptional pathways. Recent studies have identified functional, promoter polymorphisms in the human MIF gene that control its level of expression and that now are being associated with the incidence or the severity of different inflammatory diseases. The different promoter-based MIF alleles appear to exist in a balanced polymorphism that may broadly control innate responsiveness in the human population. These alleles also show significant population stratification, suggesting that the MIF locus may have been subject to different selective pressure over time. The evolutionary persistence of functionally distinct MIF alleles may ensure an essential degree of variation in innate responsiveness for human immunity.