Numerous studies have previously shown the efficiency of stem cell therapy in recovering the infarcted myocardium, by reducing the infarct size and improving the overall global function. However, the functional improvements observed in almost all cases were short-termed and many clinical trials showed that there were no long term relevant differences between infarcted myocardium with and without cell transplant. Moreover, studies monitoring cell engraftment after transplantation reported that cells were poorly retained into the heart and their large majority died posttransplantation, thus explaining the transient nature of the improvements. In these settings, it is likely that the improvement in the cardiac function is not due to the myocardial structure regeneration but rather to the biomolecules secreted by stem cells, which can improve the ventricular remodelling by attenuating the inflammation and promoting vascularisation and cell survival. This conclusion has prompted a re-consideration of stem cell field and imposed the stringency of understanding how stem cells respond to the host environment and differentiate toward a specific cell phenotype. This review is focused on the behaviour of mesenchymal stem cells after transplantation into the myocardial infarction and the molecular changes appeared in the infarcted environment that complicate the cross-talk between transplanted and host cells.