Emerging evidence suggests a pivotal role of macrophage migration inhibitory factor (MIF) in the systemic inflammatory immune response. MIF is located in various cell types and rapidly released after different stimuli like inflammation, surgical stress or ischemia and reperfusion. MIF is a known key player in the inflammatory response and contributes to several biological functions including the control of cell cycle (through activation of ERK1/2), sensing of pathogen stimuli (upregulation of TLR4 expression), recruitment of various immune cells (neutrophils, monocytes) and prevention of p53-mediated apoptosis of macrophages. While MIF`s pro-inflammatory effects are crucial for an effective host defense, elevated MIF levels were repeatedly shown to be associated with the development of organ dysfunction and deleterious sequelae. Even more puzzling, increasing evidence indicates a protective role of this pleiotropic cytokine during ischemia and reperfusion injury in the myocardium. This review focuses on new insights regarding the biological significance of MIF release in the context of critical illness and ischemia/ reperfusion.