Growing evidence links type 2 diabetes to a state of low-grade chronic inflammation, and it has been suggested that interleukin (IL)-6 promotes insulin resistance due to the observation that plasma- IL-6 is often elevated in patients with metabolic disease. However, it is now well known that IL-6 is rapidly released into the circulation following exercise and from a simplistic physio-logical point of view, it seems paradoxical that working muscle would release a factor that inhibits insulin signalling when insulin action is enhanced in the immediate post-exercise period. It is now well acknowledged that the IL-6 gene is rapidly activated during exercise and that the ac-tivation of this gene is further enhanced when muscle glycogen content is low. IL-6 is produced by contracting muscle fibers and released into the circulation, where it works in a hormone-like fash-ion. Acute IL-6 administration to humans increases insulin-stimulated glucose disposal and fatty acid oxidation in vivo, and IL-6 has strong anti-inflammatory effects. Results from IL-6KO mice indicate that IL-6 can activate AMPK in muscle and adipose tissue, and that this contributes to, but does not fully account for, the increase in AMPK activity in these tissues in response to exercise. They also suggest that a genetic lack of IL-6 is associated with a decrease in AMPK activity. In vitro studies have demonstrated that IL-6 increases both basal and insulin stimulated glucose uptake, acetyl co-A carboxylase and fatty acid oxidation in mock, but not AMPK double negative cells, indicating that the metabolic effects of IL-6 are mediated by AMPK. Our data challenge the commonly held view that IL-6 induces insulin resistance in all circum-stances and suggest that ligands that activate the heterodimeric IL-6R/gp130b receptor complex in muscle and fat cells are a viable drug target to treat peripheral insulin resistance.