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Objective: Ghrelin is emerging as a promising therapeutic option for heart failure (HF) due to its potent inotropic, anabolic, and cardioprotective properties. This review aims to critically examine the available clinical evidence on ghrelin therapy in HF, while also incorporating key findings from preclinical studies that support its therapeutic potential., Methods: A comprehensive search was conducted in PubMed and the Cochrane Library up to September 15, 2024, using the keywords "heart failure" and "ghrelin." From 247 identified records, four randomized controlled trials, one open-label trial, one observational study, and key preclinical studies were included. Two independent authors performed the screening and quality assessment, with any discrepancies resolved through consensus., Results: Clinical trials investigating ghrelin's acute effects in HF patients have demonstrated significant improvements in cardiac output, ranging from 15% to 30%. Moreover, one study showed that a 3-week course of ghrelin therapy significantly increased maximal oxygen consumption, lean body mass, and grip strength in HF patients. Preclinical studies further support these clinical findings, highlighting additional benefits of ghrelin, including modulation of the autonomic nervous system, promotion of vasodilation, enhancement of endothelial function, prevention of myocardial remodeling, reduction of arrhythmogenic risk, and increased muscle mass in HF models., Conclusions: Ghrelin is a promising therapeutic option for HF, particularly as an inotropic agent with multifaceted benefits, including autonomic nervous system modulation, anabolic effects, and metabolic regulation. However, further trials are required to confirm its long-term efficacy and safety and assess whether its benefits can translate into reductions in hard clinical endpoints., (© 2025 The Author(s). Clinical Endocrinology published by John Wiley & Sons Ltd.)