Myofibroblasts have characteristics of fibroblasts and smooth muscle cells: they produce extracellular matrix and are able to contract. In so doing, they can contribute to tissue replacement and interstitial fibrosis following cardiac injury. The scar formed after myocardial injury is no longer considered to be passive tissue; it is an active playground where myofibroblasts play a role in collagen turnover and scar contraction. Maintaining the extracellular matrix in the scar is essential and can prevent dilatation of the infarct area leading to heart failure. On the other hand, extracellular matrix deposition at sites remote from the infarct area can lead to cardiac stiffness, an inevitable process of myocardial remodeling that occurs in the aftermath of myocardial infarction and constitutes the basis of the development of heart failure. Defining molecular targets on myofibroblasts in conjunction with establishing the feasibility of molecular imaging of these cells might facilitate the early detection and treatment of patients who are at risk of developing heart failure after myocardial infarction.