Background: Ischemic stroke (IS) and acute myocardial infarction require emergency reperfusion tissue in order to improve functional outcome. Intra-arterial thrombectomy recently showed very encouraging improvement in IS patients' outcome. However, endovascular methods enhancing reperfusion may expose patients to increase in ischemic reperfusion injury. Experimental evidence indicates that brain ischemic reperfusion injury may be attenuated by ischemic pre- and postconditioning. The opening of mitochondrial permeability transition pore plays a critical role in the onset of reperfusion damage. This mechanism can be inhibited by immunosuppressive drugs like cyclosporine A (CsA). Summary: In this review, we present existing experimental and clinical data suggesting that conditioning interventions may prevent brain ischemic reperfusion injury and future challenge for neuroprotection by CsA in acute IS. Key Messages: The concept of conditioning has been recently investigated clinically but to a lesser extent in the realm of IS. Recent experimental and phase II clinical research has suggested potential neuroprotective properties of cyclosporine; however, further larger clinical trials are needed to demonstrate that CsA improves clinical outcome in acute IS patients.