Ischemic heart disease (IHD) represents the leading cause of morbidity and mortality worldwide. Therapy options generally aim at restoring the blood flow to the heart muscle and relieve the ischemic insult. Paradoxically, coronary artery reperfusion itself, both during emergency intervention in ST segment elevation myocardial infarction (STEMI) patients or in the setting of elective cardiac surgery, damages the heart muscle, a phenomenon known as myocardial ischemia-reperfusion (I/R) injury (IRI). Ischemic preconditioning (IPC) is defined by episodes of ‘sub-lethal’ ischemia and reperfusion prior to prolonged coronary artery occlusion. It has been extensively studied as a promising approach to attenuate IRI, but two recent multicenter clinical trials of remote IPC (RIPC) on clinical outcomes have been disappointing. Macrophage migration-inhibitory factor (MIF) is a structurally unique chemokine-like inflammatory cytokine. MIF is pro-atherogenic, but has a complex function in the ischemic heart with a surprising potential as a local cardioprotective factor in early myocardial ischemia. A recent paper published in Clinical Science by Ruze et al. , now suggests that MIF could be a key player mediating IPC in the ischemic heart. Employing a Mif gene knockout mouse model, the study indicates a role for endogenous MIF in IPC-mediated protection from myocardial IRI. It could assist in understanding how this atypical cytokine controls ischemic heart pathologies and may set the stage for novel MIF-based therapeutic strategies in IHD.