Background - After an acute ST-segment elevation myocardial infarction (STEMI), early and successful myocardial reperfusion with primary percutaneous coronary intervention (PCI) is the most effective strategy for reducing the infarct size and improving clinical outcome. The process of restoring blood flow to the ischemic myocardium, however, can induce injury per se, paradoxically increasing the extent of final infarction (i.e., reperfusion injury). Research has been focusing for years on a strategy to effectively counteract reperfusion injury and, thereby, reduce the final infarct size with salutary effects on clinical outcome. Robust experimental evidences support Glucose-Insulin-Potassium (GIK) as an effective cardioprotective agent being capable to metabolically protect the myocardium against ischemia and ischemia/reperfusion injury. These benefits are clearly related to the time that GIK is administered in the course of cardiac ischemia, with effectiveness increasing with early administration. However, clinical trials in the reperfusion era have lost the opportunity to translate the beneficial effects seen in the laboratory to the clinical setting, because of the unacceptably prolonged delay from the onset of ischemic symptoms to GIK administration. A properly-designed prospective trial with double-blinded randomization to placebo or GIK in the out-of-hospital setting would straightforwardly overcome this limitation, thereby providing convincing evidences in favor or disfavor of GIK treatment. Notable, GIK is an un-expensive compound, and upon the verification of its efficacy, GIK treatment would be ready for primetime clinical application with matchless cost/effectiveness profile.