Heart failure (HF) with preserved ejection fraction (HFpEF) or “diastolic HF” accounts for approximately half of HF cases. To date, neurohumoral antagonists have failed to show a significant benefit on clinical outcomes in HFpEF. While our understanding of the pathophysiology of HFpEF continues to develop, multiple therapeutic targets have been identified in HFpEF which may be modifiable by augmentation of the intracellular second messenger cyclic guanosine monophosphate (cGMP) via phosphodiesterase-5 inhibition (PDE5I) in HFpEF. The PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX trial; clinicaltrials.gov NCT00763867) is being conducted within the NHLBI sponsored HF clinical research network and tests the hypothesis that chronic PDE5I (sildenafil® 20 mg tid for 12 weeks followed by 60 mg tid for 12 weeks) improves exercise capacity and clinical status in patients with HFpEF. Here we provide the rationale for RELAX by summarizing the pathophysiologic derangements in HFpEF and the evidence that PDE5I may ameliorate these derangements. The design of the RELAX trial is described and the rationale for the primary endpoint in RELAX (change in peak oxygen consumption) is provided.