Myocardial infarction (MI) results in alterations in cardiac structure and function that not only impact the infarcted area, but also result in changes in the remote, remodelled myocardium. These changes also encompass structural changes in the coronary vascular tree and an increase in extravascular compressive forces acting on the microcirculation, thereby blunting myocardial flow reserve. Moreover, regulation of microvascular tone in the remote coronary vasculature is altered after MI. The alterations in regulation of microvascular tone appear to be principally the result of a loss of NO bioavailability in conjunction with an increased reactive oxygen species production. Interestingly, a reduced influence of a number of vasoconstrictors, including PDE5 and endothelin, serves to blunt the abnormalities in myocardial oxygen balance in remodelled myocardium after MI. Nevertheless, the overall changes in control of microvascular tone perturb the myocardial perfusion, resulting in impaired myocardial O-2 delivery to the non-infarcted regions. The accompanying cardiomyocyte contractile dysfunction and/or enhanced apoptosis may contribute to the progression of cardiac dysfunction after MI.