Although the introduction of angiotensin-converting enzyme (ACE) inhibitors and β-adrenergic blockers has resulted in significant improvements in the management of heart failure (HF), morbidity and mortality remain high. Therefore, additional approaches have been sought to discover newer agents that might add incremental benefit. Although not all of these approaches have been successful, there have been some notable new approaches to therapy that have shown benefit or may be promising in terms of additional benefit. Most of these agents are targeted to achieve a more global neurohormonal blockade aiming to reduce or potentially reverse the ventricular remodeling process that occurs in HF. Some of the newer approaches aim for targets other than neurohormonal systems, eg, effects on myocardial metabolism or the vasculature. This article reviews the latest advances in pharmacologic therapy in HF, looking at several trials that may have a significant impact on the treatment of HF. We also discuss several newer agents with promising potential in HF management.