Despite treatment with conventional agents, a high proportion of patients with ischemic cardiomyopathy continue to have symptoms. Moreover, a substantial proportion shows progressive contractile dysfunction leading to left ventricular (LV) enlargement and heart failure. Therefore, a need exists for new treatments for ischemic cardiomyopathy that tackle mechanisms other than those already addressed by conventional agents. Emerging evidence suggests that in patients with ischemic cardiomyopathy, LV dysfunction develops as a result of alterations in substrate metabolism, which contribute to contractile dysfunction and the progression of LV remodeling. Trimetazidine, a novel pharmacologic agent that acts on myocardial metabolic pathways, appears to protect the heart from the deleterious effects of ischemia, and it has been shown to enhance LV contractility in patients with stunned or hibernating myocardium. This article reviews recent clinical trials that have assessed the therapeutic role of trimetazidine in patients with ischemic cardiomyopathy. Trimetazidine has been shown to improve symptoms and LV ejection fraction and to have a beneficial effect on the inflammatory profile and endothelial function in these patients. These results suggest that trimetazidine is a useful adjunct to our current armamentarium for the treatment of patients with ischemic cardiomyopathy.