Abstract: Many studies have shown that tumor necrosis factor-α (TNF-α) plays a self-contradictory role in myocardial ischemia/reperfusion (I/R) injury, i.e., protection and injury. The self-contradictory effect actually takes place in different periods of myocardial I/R mediated by the different signal transduction pathways. Acute I/R damages coronary endothelia in ischemia zone and induces the adherence of macrophages and lymphocytes to release soluble TNFα (sTNFα). High levels of sTNF-α activate tumor necrosis factor receptor 1 (TNFR1) and its downstream signal transduction pathways to cause cardiomyocyte apoptosis. In the remodeling or repairing period of myocardial I/R, althought sTNF-α level is higher than that of physiological condition in plasma, the increased soluble TNFR neutralizes sTNF-α to prevent it from injuring normal myocardial tissue in the remote zone. The local ischemia of myocardium stimulates cardiomyocytes and fibroblasts to synthesize transmembrane TNF-α, which then activates tumor necrosis factor receptor 2 and its downstream transduction pathway in nearby cells. Therefore, calcium transport and contractile function of cardiomyocytes enhanced and survived cardiomyocytes in the border zone are saved. The local transmembrane TNF-α can recruit mesenchymal stem cells to release cytokine and growth factors, which improve cardiac function. Transmembrane TNF-α depresses histone deacetylases 1 (HDAC1). HDAC1 provides a molecular switch for determining cellular survival in the TNF-α pathway via modulating NF-κB gene transcription. Transmembrane TNFα also results in resident cardiac stem cells differentiated toward cardiomyocytes and repair the injured myocardium tissue.