Transient global or forebrain ischemia leads to severe brain damage following delayed neuronal cell death. We previously reported that cyclosporin A (CsA) provides near total suppression of brain damage in rat forebrain ischemia when allowed to pass the blood brain barrier, whereas Tacrolimus (FK506) is considerably less effective. We demonstrate herein that when administered prior to ischemic insult, both immunosuppressants equally block calcineurin, a type 2B Ser/Thr phosphatase, and efficiently inhibit dephosphorylation of pro-apoptotic protein Bad. CsA demonstrates more potent anti-ischemic effects than FK506, partially attributable to amelioration of mitochondrial damage as assayed in vivo and in vitro. These results suggest that pathways including calcineurin and cyclophilins, particularly mitochondrial cyclophilin D, play pivotal roles in ischemic brain damage. Since previous results have shown that CsA is efficacious also when administered after focal ischemia, the present findings give hints to clinical applications for new drugs for the treatment of ischemic damage in the brain as well as in the heart and liver.