Heart failure therapy has seen many advances over the last 40 years and has rapidly expanded beyond diuretics and digoxin to include several new mechanisms of action and devices whose efficacy had been demonstrated in large clinical trials. The evidence for their use is thoroughly summarized and discussed in current heart failure treatment guidelines and is not the subject of this review. Despite these advances, the mortality and morbidity in heart failure patients is still substantial, and there remains a need to develop new heart failure therapies. Recognizing that advances in medical therapy are often driven by the introduction of drugs with novel mechanisms of action, here we provide an overview of investigative heart failure drugs with novel mechanisms of action that are the subject of ongoing clinical trials.