The syndrome of heart failure in the setting of normal ejection fraction (HFNEF) is manifest in a clinically heterogeneous group of patients with multiple and varied comorbid conditions. In this report, we review available data derived from pressure-volume (PV) analyses in patients with and in animal models of HFNEF. Pressure-volume analysis of ventricular function is challenging in the clinical setting but provides unique insights into the systolic, diastolic, and overall pumping characteristics of the heart. Results of such analyses have thus far been limited to small cohorts of patients but suggest that different cohorts of patients with HFNEF having PV relations that imply different pathophysiologic mechanisms exist. This emphasizes the need to take a view of this syndrome, which extends beyond diastolic dysfunction, particularly when it comes to proposing and investigating therapeutic targets. We therefore propose that progress can be made in advancing therapeutics for HFNEF if it is appreciated that different underlying pathophysiologic mechanisms may be important in different cohorts and if attention expands beyond diastolic dysfunction as the sole target. Similar to the success that was achieved in advancing therapeutics for systolic heart failure when attention shifted away from the heart to the neurohormonal and renal axes, our interpretation of data in human beings and in animal models suggests that addressing similar targets (perhaps not in exactly the same manner) may prove to be fruitful, at least for some patients with HFNEF as well.