Heart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic problem affecting more than half of the patients with heart failure (HF). HFpEF has a significant morbidity and mortality and so far no treatment has been clearly demonstrated to improve the outcomes in HFpEF, in contrast to the efficacy of treatment in heart failure with reduced ejection fraction (HFrEF).The failure of proven beneficial drugs in HFrEF to influence the outcome of patients with HFpEF could be related to the heterogeneity of the disease, its various phenotypes and multifactorial pathophysiology, incompletely elucidated yet. The diagnosis of HFpEF could be demanding or even inaccurate. Moreover, the therapeutic strategies were influenced by different cut-offs used to define preserved ejection fraction (EF). From this perspective, the current guidelines have classified HFpEF by an EF ≥ 50%, together with a distinct entity, heart failure with mid-range ejection fraction (HFmrEF), defined by an EF ranging from 41-49%.New therapies have been developed to interfere with the mediator pathways of HFpEF at the cellular and molecular level, including mineralocorticoid receptor antagonists, soluble guanylate cyclase stimulators, or angiotensin receptor-neprilysin inhibitors. A number of antidiabetic drugs, such as sodium/glucose cotransporter 2 inhibitors and dipeptidyl peptidase-4 inhibitors are promising options, being under research in large clinical trials. Until the results of ongoing trials shed light on these therapies, guidelines recommend empirical treatment for established HFpEF, and emphasize the crucial role of addressing cardiovascular comorbidities leading to HFpEF, in particular arterial hypertension.