OBJECTIVES: To review the role of macrophage migration inhibitory factor (MIF) in host responses to infection and to explore the potential of MIF as a novel target for therapeutic intervention in patients with severe sepsis and septic shock. DATA SOURCES: Published articles on the role of MIF in innate immune responses against microbial pathogens. DATA SUMMARY: MIF has emerged recently as an important effector molecule of the innate immune system. MIF is expressed constitutively by monocytes/macrophages, T cells, B cells, endocrine cells, and epithelial cells. Microbial toxins and cytokines are powerful inducers of MIF release by immune cells. MIF expression is up-regulated during the course of inflammatory and infectious diseases and was found to play an important role in the pathogenesis of sepsis and septic shock. CONCLUSION: Given the role of MIF in innate immune responses against microbial pathogens and in the regulation of inflammatory responses, modulation of MIF production or neutralization of its activity may offer new therapeutic options for the management of patients with sepsis.