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Myocardial ischemia and reperfusion (I/R) lead to an inflammatory response that causes cardiac injury and remodeling. However, increasing evidence suggests this is an over-simplified view. Several proinflammatory cytokines, including tumor necrosis factor-α, interleukin-1α, interleukin-6, macrophage migration inhibitory factor and D-dopachrome tautomerase have been shown to improve cell survival and compensate energy deprivation during I/R. This review summarizes the recent findings that support protective role of proinflammatory cytokines against cardiac injury during acute I/R, as well as therapeutic ramifications of these findings.