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In this article, we review the literature regarding the role of c-Jun N-terminal kinases(JNKs) in cerebral and myocardial ischemia/reperfusion injury. Numerous studiesdemonstrate that JNK-mediated signaling pathways play an essential role in cerebraland myocardial ischemia/reperfusion injury. JNK-associated mechanisms are involved inpreconditioning and post-conditioning of the heart and the brain. The literature and ourown studies suggest that JNK inhibitors may exert cardioprotective and neuroprotectiveproperties. The effects of modulating the JNK-depending pathways in the brain andthe heart are reviewed. Cardioprotective and neuroprotective mechanisms of JNKinhibitors are discussed in detail including synthetic small molecule inhibitors (AS601245,SP600125, IQ-1S, and SR-3306), ion channel inhibitor GsMTx4, JNK-interactingproteins, inhibitors of mixed-lineage kinase (MLK) and MLK-interacting proteins, inhibitorsof glutamate receptors, nitric oxide (NO) donors, and anesthetics. The role of JNKs inischemia/reperfusion injury of the heart in diabetes mellitus is discussed in the contextof comorbidities. According to reviewed literature, JNKs represent promising therapeutictargets for protection of the brain and the heart against ischemic stroke and myocardialinfarction, respectively. However, different members of the JNK family exert diversephysiological properties which may not allow for systemic administration of non-specificJNK inhibitors for therapeutic purposes. Currently available candidate JNK inhibitors withhigh therapeutic potential are identified. The further search for selective JNK3 inhibitorsremains an important task.