Heart failure (HF) is a common clinical syndrome that affects more than 23 million individuals worldwide. Despite the marked advances in its management, the mortality rates in HF patients have remained unacceptably high. Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription regulators, involved in the regulation of fatty acid and glucose metabolism. PPAR agonists are currently used for the treatment of type II diabetes mellitus and hyperlipidemia; however, their role as therapeutic agents for HF remains under investigation. Preclinical studies have shown that pharmacological modulation of PPARs can upregulate the expression of fatty acid oxidation genes in cardiomyocytes. Moreover, PPAR agonists were proven able to improve ventricular contractility and reduce cardiac remodelling in animal models through their anti-inflammatory, anti-oxidant, anti-fibrotic, and anti-apoptotic activities. Whether these effects can be replicated in humans is yet to be proven. This article reviews the interactions of PPARs with the pathophysiological mechanisms of HF and how the pharmacological modulation of these receptors can be of benefit for HF patients.