<p>Heart failure (HF) affects nearly 8 million individuals in the USA, with approximately half diagnosed with heart failure with preserved ejection fraction (HFpEF). HFpEF is associated with high morbidity and mortality, with fewer than 25% of patients surviving beyond 5&#xa0;years after diagnosis. Historically, poor outcomes have been largely attributed to a lack of effective disease-modifying therapies. However, the past 5&#xa0;years have marked a transformative era in HFpEF management, with multiple landmark clinical trials demonstrating benefits for novel therapeutic classes. These include sodium-glucose cotransporter 2 inhibitors (SGLT2i), non-steroidal mineralocorticoid receptor antagonists (Ns-MRAs), and glucagon-like peptide-1 (GLP-1) receptor agonists, particularly for the obesity-related HFpEF phenotype. In this review, we summarize the evolution of HFpEF therapeutics, from traditional heart failure treatments with limited efficacy to emerging targeted therapies, highlighting the latest evidence shaping a modern, comprehensive approach to HFpEF management.</p> Graphical Abstract <p>Heart failure with preserved ejection fraction therapeutics in the comprehensive and contemporary era. Abbreviations: HHF, hospitalization for heart failure; CV, cardiovascular; PRO, patient reported outcomes; EF, ejection fraction; WRF, worsening renal function; Ns-MRA, non-steroidal mineralocorticoid receptor antagonist, sMRA, steroidal mineralocorticoid receptor antagonist; ACEi: angiotensin converting enzyme inhibitor; ARB, aldosterone receptor blocker; ARNi, angiotensin neprilysin inhibitor, GLP1a: glucagon-like-peptide agonist, GIP: glucose-dependent insulinotropic polypeptide; SGLT2i, sodium-glucose cotransporter 2 inhibitors</p> <p></p>