Ventricular remodeling after myocardial infarction is defined as progressive chamber dilation and wall thinning, which leads to functional compromise. Remodeling is mediated by active processes of inflammation, fibrosis, and cardiomyocyte dropout over the weeks and months after infarction, and, therefore, provides a large temporal therapeutic window. In experimental models, interruption of molecular and physiological pathways that contribute to cardiomyocyte loss, and the resulting unfavorable ventricular geometry, can abrogate remodeling and prevent or improve heart failure. Remodeling is multifactorial and involves several parallel cellular pathways, which means many potential therapeutic targets exist. Of late, much attention has been given to the development of cell-based therapies; however, the abundant, promising pharmacotherapeutic developments should not be overlooked. This Review examines developments in pharmacological treatment of ventricular remodeling in preclinical models of myocardial infarction-specifically, disruption of the renin-angiotensin-aldosterone system through direct renin inhibition and blockade of aldosterone synthesis and/or uptake, enhancement of endothelial nitric oxide synthase synthesis, G-protein receptor kinase inhibition, administration of erythropoietin, and interruption of apoptosis-and highlights the challenge of translating these successes to treatment of human disease. Therapeutic targeting of multiple organ systems involved in recovery after myocardial infarction might prove to be the best approach to improve patients' cardiac outcome.