Disrupted fatty acid metabolism is one of the most important metabolic features in heart failure. The heart obtains energy from fatty acids via oxidation. However, heart failure results in markedly decreased fatty acid oxidation and is accompanied by the accumulation of excess lipid moieties that lead to cardiac lipotoxicity. Herein, we summarized and discussed the current understanding of the integrated regulation of fatty acid metabolism (including fatty acid uptake, lipogenesis, lipolysis, and fatty acid oxidation) in the pathogenesis of heart failure. The functions of many enzymes and regulatory factors in fatty acid homeostasis were characterized. We reviewed their contributions to the development of heart failure and highlighted potential targets that may serve as promising new therapeutic strategies.