Heart failure with preserved ejection fraction (HFpEF) is a frustrating problem. Although stiffening of the heart is common and can be frequently demonstrated, other mechanisms have been implicated to account for the common symptoms of exertional dyspnea and intolerance. However, what remains common to eventually all patients with HFpEF is what defines heart failure clinically, namely, volume overload. Surprisingly, why there is avidity for salt and water in HFpEF remains largely unexplored. In heart failure with reduced ejection fraction, consistent and predictable hemodynamic abnormalities lead to activation and sustained stimulation of neurohormonal systems that result in renal retention of sodium and water. Interruption of this cascade slows disease progression in the heart and reduces clinical events, such as heart failure hospitalizations, a clinical marker of salt and water retention. In contrast, there is no unifying paradigm for the tendency toward volume overload in HFpEF. The centrality of neurohormonal activation in HFpEF as an explanation is debatable. First, most invasive hemodynamic studies of HFpEF (excluding pure forms of HFpEF such as restrictive cardiomyopathies) do not find low cardiac output or arterial underfilling, accepted stimuli for salt and water retention. Second, limited studies that have directly measured sodium and fluid avid neurohormones provide conflicting data. Moreover, although natriuretic peptides often are elevated, the magnitude of elevation is often modest, particularly when viewed relative to the degree of volume overload. Three, antagonism of multiple …