To discuss recent findings with regard to the regulation of muscle-derived interleukin-6 as well as the possible physiological and metabolic roles of interleukin-6 in response to exercise. Contraction-induced transcription and release of interleukin-6 is primarily regulated by an altered intramuscular milieu in response to exercise. Accordingly, changes in calcium homeostasis, impaired glucose availability and increased formation of reactive oxygen species are all associated with exercise and capable of activating transcription factors known to regulate interleukin-6 synthesis. Acute interleukin-6 administration to humans increases lipolysis, fat oxidation and insulin-mediated glucose disposal. Adenosine monophosphate-activated protein kinase activation by interleukin-6 appears to play an important role in modulating some of these metabolic effects. Interleukin-6 facilitates an antiinflammatory milieu and may exert some of its biological effects via inhibition of the proinflammatory cytokine tumor necrosis factor-alpha. The discovery of contracting muscle as a cytokine-producing organ opens a new paradigm: skeletal muscle is an endocrine organ that in response to contractions produces and releases 'myokines', which subsequently can modulate the metabolic and immunological response to exercise in several tissues. In our view, interleukin-6 may be one of several myokines.