Cardiovascular disease remains the leading cause of mortality in the developed world. It is estimated that 5 million Americans suffer from heart failure (HF), and roughly 550,000 new cases are diagnosed annually. Studies have found that 40% to 71% of patients who have HF have relatively preserved systolic functions, or diastolic heart failure (DHF). Although there are abundant data to guide the treatment of heart failure and systolic dysfunction (systolic HF), evidence-based data are lacking in the management of DHF. This article examines the role of neurohormonal modulators in the management of DHF.