Interleukin-6 (IL-6) is produced locally in working skeletal muscle and can account for the increase in plasma IL-6 during exercise. The production of IL-6 during exercise is related to the intensity and duration of the exercise, and low muscle glycogen content stimulates the production. Muscle-derived IL-6 is released into the circulation during exercise in high amounts and is likely to work in a hormone-like fashion, exerting an effect on the liver and adipose tissue, thereby contributing to the maintenance of glucose homeostasis during exercise and mediating exercise-induced lipolysis. Muscle-derived IL-6 may also work to inhibit the effects of pro-inflammatory cytokines such as tumour necrosis factor alpha. The latter cytokine is produced by adipose tissue and inflammatory cells and appears to play a pathogenetic role in insulin resistance and atherogenesis.