It is now recognized that contracting skeletal muscle may synthesize and release interleukin-6 (IL-6) into the interstitium as well as into the systemic circulation in response to a bout of exercise. Although several sources of IL-6 have been demonstrated, contracting muscles contributes to most of the IL-6 present in the circulation in response to exercise. The magnitude of the exercise-induced IL-6 response is dependent on intensity and especially duration of the exercise, while the mode of exercise has little effect. Several mechanisms may link muscle contractions to IL-6 synthesis: Changes in calcium homeostasis, impaired glucose availability, and increased formation of reactive oxygen species (ROS) are all capable of activating transcription factors known to regulate IL-6 synthesis. Via its effects on liver, adipose tissue, hypothalamic-pituitary-adrenal (HPA) axis and leukocytes, IL-6 may modulate the immunological and metabolic response to exercise. However, prolonged exercise involving a significant muscle mass in the contractile activity is necessary in order to produce a marked systemic IL-6 response. Furthermore, exercise training may reduce basal IL-6 production as well as the magnitude of the acute exercise IL-6 response by counteracting several potential stimuli of IL-6. Accordingly, a decreased plasma IL-6 concentration at rest as well as in response to exercise appears to characterize normal training adaptation.