Myocardial infarction necessitates new therapeutic interventions, since it still results in high morbidity and mortality worldwide. Reperfusion therapy itself results in (acceleration of) apoptosis, called myocardial ischemia/reperfusion (I/R) injury. For several decades it is known that the inflammatory response during reperfusion is the major cause of myocardial I/R injury. Therapeutic options are limited by lack of (detailed) understanding of intra- and intercellular mechanisms between inflammatory cells and cardiomyocytes. Furthermore, clinical trials generally fail to reproduce experimental successes, because essential factors are not taken into account in animal studies: risk factor for coronary artery disease, duration of ischemia and reperfusion, time of intervention. Above all, there is no specific therapeutic target for inhibiting the inflammatory response, in which cardiomyocytes are involved. The identification of Toll-like receptors (TLRs) on cardiomyocytes, has given rise to, not only new insights on the inflammatory response initiated by cardiomyocytes themselves, but also provided potential targets to reduce myocardial I/R injury. Experimental and clinical studies show that inflammatory responses are also involved in tissue repair responses. Since certain TLRs are expressed on inflammatory cells and cardiomyocytes, it ensures specific targeting of either detrimental effects or tissue repair responses in the inflammatory response during reperfusion. Which TLRs are involved in the ‘good’ and which in the ‘bad’ effects of the inflammatory response remains to be addressed. This review will discuss both experimental and clinical research on inflammatory reactions that occur after myocardial ischemia/ reperfusion (I/R). Data and conclusions concerning potential therapeutic targets in both experimental as clinical research settings will be reviewed.