After an episode of myocardial infarction (MI), patients remain at risk for recurrent ischemic events, heart failure (HF), and sudden death. Post-MI patients with left ventricular systolic dysfunction (LVSD) have an even greater risk of mortality and morbidity. Randomized clinical trials that included post-MI patients with LVSD have demonstrated that pharmacologic therapies aimed at preventing post-MI remodeling with neurohormonal antagonists can significantly improve short- and long-term outcomes, including death, reinfarction, and worsening HF. Recent trials have also demonstrated benefits in terms of cardiovascular event reduction with effective antithrombotic therapies and cholesterol-lowering agents in post-MI setting, especially in patients at very high risk such as those with LVSD. This paper reviews clinical trials that included post-MI patients with LVSD, with or without signs and symptoms of HF, assessing the efficacy of established and emerging pharmacological therapies.