Interleukin-6 (IL-6) is a multifunctional cytokine that exerts its modulatory effects on cells that express membrane bound IL-6 receptors; however, IL-6 in a complex with soluble IL-6R can bind to any cell that express glycoprotein 130 (gp130). Thus, all cell types may respond to the pro- as well as anti-inflammatory properties of IL-6. Since the first report of acute exercise-induced increase in plasma IL-6 in the early 1990s, scientists have tried to elucidate the factors that influence the magnitude of change of plasma IL-6, as well as the possible biological roles of this cytokine. Evidence suggests that exercise intensity and duration as well as the form of contraction (e.g., eccentric or concentric) and muscle damage all influence IL-6 response to acute exercise. However, data on training status and performance on plasma IL-6 concentration changes during exercise are more inconclusive, as discussed in this review. In the last decade, most of the studies have focused on IL-6 as an 'energy sensor' possibly secreted by skeletal muscle that activates glycogenolysis in the liver and lipolysis in fat tissue in order to provide muscle with the growing energy demands during exercise.