Epicardial adipose tissue is a unique and multifaceted fat depot with local and systemic effects. This tissue is distinguished from other visceral fat depots by a number of anatomical and metabolic features, such as increased fatty acid metabolism and a unique transcriptome enriched in genes that are associated with inflammation and endothelial function. Epicardial fat and the heart share an unobstructed microcirculation, which suggests these tissues might interact. Under normal physiological conditions, epicardial fat has metabolic, thermogenic (similar to brown fat) and mechanical (cardioprotective) characteristics. Development of pathological conditions might drive the phenotype of epicardial fat such that it becomes harmful to the myocardium and the coronary arteries. The equilibrium between protective and detrimental effects of this tissue is fragile. Expression of the epicardial-fat-specific transcriptome is downregulated in the presence of severe and advanced coronary artery disease. Improved local vascularization, weight loss and targeted medications can restore the protective physiological functions of epicardial fat. Measurements of epicardial fat have several important applications in the clinical setting: accurate measurement of its thickness or volume is correlated with visceral adiposity, coronary artery disease, the metabolic syndrome, fatty liver disease and cardiac changes. On account of this simple clinical assessment, epicardial fat is a reliable marker of cardiovascular risk and an appealing surrogate for assessing the efficacy of drugs that modulate adipose tissues.