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Until recently, patients with heart failure and preserved ejection fraction (HFprEF) have been excluded from nearly all large clinical trials in heart failure. Based on the conjecture that this clinical picture of heart failure, also known as diastolic heart failure, may be different from other forms of heart failure, several recent and ongoing clinical trials have targeted more specifically this patient population. The present review critically re-evaluates the pathophysiological rationale for such trials.Novel techniques to evaluate cardiac performance have revealed that HFprEF is a consequence of significant systolic dysfunction of the ventricular muscular pump in the presence of a preserved performance of the ventricular hemodynamic pump. Diastolic and systolic heart failure are the mere extremes of a spectrum of different phenotypes of one and the same disease. Ongoing research explores the various disease modifiers, or protective pathways, that delay the progression of remodeling in patients with HFprEF. Although, currently, therapy to improve the prognosis of HFprEF is essentially the same as for other forms of heart failure, the latter ongoing studies may help, in addition, in developing novel and more patient-specific therapeutic strategies in these patients.HFprEF constitutes a heterogenous group of different phenotypes within one continuous spectrum reflecting heart failure as one disease entity. No pathophysiological basis currently warrants setting up empirical clinical trials based on an arbitrary subdivision of patients with heart failure.