The article reviews the role of macrophage migration inhibitory factor (MIF) in innate immunity and its implications for therapeutic interventions. MIF, initially identified as a cytokine, has emerged as a crucial regulator of the host's antimicrobial and stress responses. It is expressed constitutively by immune and endocrine cells, as well as by tissues in direct contact with the external environment, suggesting its importance in early host defense. MIF upregulates Toll-like receptor 4 (TLR4) expression, enabling rapid detection of endotoxins and Gram-negative bacteria. MIF also promotes pro-inflammatory responses by activating the extracellular signal-regulated kinase 1/2 (ERK1/ERK2) pathway, enhancing phospholipase A2 (PLA2) activity, and inducing prostaglandin E2 (PGE2) production. Additionally, MIF counteracts the immunosuppressive effects of glucocorticoids, and it inhibits p53 activity to prevent apoptosis. MIF is implicated in the pathogenesis of sepsis, acute respiratory distress syndrome (ARDS), asthma, arthritis, and other inflammatory and autoimmune diseases. High levels of MIF correlate with disease severity, and neutralizing MIF-specific antibodies can improve outcomes in experimental models. The article discusses the potential of MIF-directed therapies for treating severe sepsis and inflammatory diseases.The article reviews the role of macrophage migration inhibitory factor (MIF) in innate immunity and its implications for therapeutic interventions. MIF, initially identified as a cytokine, has emerged as a crucial regulator of the host's antimicrobial and stress responses. It is expressed constitutively by immune and endocrine cells, as well as by tissues in direct contact with the external environment, suggesting its importance in early host defense. MIF upregulates Toll-like receptor 4 (TLR4) expression, enabling rapid detection of endotoxins and Gram-negative bacteria. MIF also promotes pro-inflammatory responses by activating the extracellular signal-regulated kinase 1/2 (ERK1/ERK2) pathway, enhancing phospholipase A2 (PLA2) activity, and inducing prostaglandin E2 (PGE2) production. Additionally, MIF counteracts the immunosuppressive effects of glucocorticoids, and it inhibits p53 activity to prevent apoptosis. MIF is implicated in the pathogenesis of sepsis, acute respiratory distress syndrome (ARDS), asthma, arthritis, and other inflammatory and autoimmune diseases. High levels of MIF correlate with disease severity, and neutralizing MIF-specific antibodies can improve outcomes in experimental models. The article discusses the potential of MIF-directed therapies for treating severe sepsis and inflammatory diseases.