In our quest for comprehensive protection of ischemic myocardium, both basic and clinical studies have lead us to examine signal transduction pathways involved in ischemia-reperfusion injury for potential therapeutic targets. In this review, we have highlighted the importance of the JAK-STAT pathway in modulating ischemia-reperfusion injury. The mechanisms linking glucose metabolism, angiotensin II, with JAK-STAT pathway in ischemic injury are explored in this review. Clearly, the studies discussed in this review provide rationale for the design and synthesis of selective blockers of JAK-STAT pathway as potential therapeutic adjuncts in protecting ischemic myocardium.