MicroRNAs (miRNAs) are small (∼22 nt) noncoding single-stranded RNA molecules that downregulate gene expression. Studies have shown that miRNAs control diverse aspects of heart disease, including hypertrophy, remodeling, heart failure, and arrhythmia. Recently, several studies have suggested that miRNAs contribute to ischemia-reperfusion injury by altering key signaling elements, thus making them potential therapeutic targets. By altering the expression of various key elements in cell survival and apoptosis [such as phosphoinositide 3-kinase (PI3K), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), Bcl-2, Mcl-1, heat shock protein (HSP)60, HSP70, HSP20, programmed cell death 4 (Pdcd4), LRRFIP1, Fas ligand (FasL), Sirt-1, etc.], miRNAs alter the response to ischemia-reperfusion injury. Studies using various in vivo, ex vivo, and in vitro models have suggested the possible involvement of miR-1, miR-21, miR-29, miR-92a, miR-133, miR-199a, and miR-320 in ischemia-reperfusion injury and/or remodeling after myocardial infarction. Thus miRNAs could be potential therapeutic targets for the treatment of heart disease. Inhibiting miRNAs by antisense strategies or pharmacological approaches is likely to emerge as an alternative and safe method for conferring short- and intermediate-term protection against ischemia-reperfusion injury.