The five current members of the thrombospondin (TSP) family can be divided in two subgroups according to their molecular architecture. TSP-1 and -2 (subgroup A) are trimeric matricellular proteins that do not contribute directly to tissue integrity, but influence cell function by modulating cell-matrix interactions, whereas TSP-3, -4 and -5 (subgroup B) are pentameric proteins. TSP-1 and TSP-2 are markedly induced in healing wounds and may regulate cellular responses important for tissue repair. TSP-1 is a crucial activator of TGF-beta, whereas both TSP-1 and TSP-2 inhibit angiogenesis. This manuscript reviews our current knowledge on the expression and role of the TSPs in healing myocardial infarcts. In both canine and murine infarcts, TSP-1 shows a strikingly selective localization in the infarct border zone. In the absence of injury, TSP-1 -/- mice exhibit normal cardiac morphology and show no evidence of myocardial inflammation. Infarcted TSP-1 -/- mice have an enhanced and protracted inflammatory response with subsequent expansion of granulation tissue in the non-infarcted area, resulting in myofibroblast infiltration into the viable myocardium neighboring the infarct. Infarcted TSP-1 -/- animals have enhanced left ventricular remodeling compared with their wildtype littermates. We suggest that TSP-1 is a critical component of the protective mechanisms induced in the infarct border zone in order to limit expansion of fibrosis into the non-infarcted myocardium. Localized TSP-1 expression may suppress expansion of the inflammatory process by activating TGF-beta or by inhibiting local angiogenesis. In addition, TSP-1-mediated inhibition of MMP activity may decrease adverse remodeling. TSP-2, on the other hand, appears to be a crucial regulator of the integrity of the cardiac matrix that is necessary for the myocardium to cope with increased loading. The expression and potential role of the pentameric TSPs in the infarcted heart remain unknown. Understanding the specific mechanisms responsible for the protective effects of TSP-1 and TSP-2 in healing infarcts may lead to novel therapeutic interventions aiming at attenuating adverse left ventricular remodeling.