Since the initial discovery that AMP-activated protein kinase (AMPK) is increased in accordance with exercise intensity, there has been significant interest in the proposed role of this ancient stress-sensing kinase to act as a critical integrative switch controlling metabolic responses. AMPK exists as a heterotrimer that consists of an α catalytic subunit (α1,α2), a scaffolding β subunit (β1, β2) and a nucleotide-binding γ subunit (γ1,γ2,γ3). The C-terminal of the β subunit contains a highly conserved α and γ subunit-binding sequence that is required for the formation of a stable, active AMPK αβγ complex. AMPK is stimulated by metabolic stresses (muscle contraction) or stresses resulting in inhibition of ATP synthesis (ischaemia, hypoxia, glucose/nutrient deprivation). The regulation of AMPK activity depends on AMP and ADP mediated phosphorylation of the α catalytic subunit at T172 by upstream kinases (which in skeletal muscle and liver is LKB1). Once activated, AMPK phosphorylates key metabolic enzymes that decrease ATP consumption (fatty acid & triglyceride synthesis) or generate ATP (glucose uptake, fatty acid oxidation) (reviewed in Ref 1). We have recently characterized the metabolic phenotype of mice lacking both AMPK β1 and β2 isoforms in muscle (Ref 2). These were the first mice completely lacking AMPK activity in skeletal muscle. The most striking phenotype of the AMPK Double Muscle Knock-Out mice (AMPK DMKO) is that these mice are nearly completely exercise intolerant. This is evidenced by our observations that when given an exercise wheel to run AMPK DMKO mice are completely inactive compared to their wildtype littermates. Similarly, during treadmill exercise AMPK DMKO mice become fatigued immediately when they start running compared to wildtype littermates that can run for several hours at the same exercise intensity. Importantly, this much greater rate of fatigue is also observed when muscles are contracted in vitro indicating that it is not due to potential issues related to blood-flow or perfusion. In addition this effect is not due to a dramatic fibre type-shift or reductions in maximal force production. As our studies have shown that there is no substitute for skeletal muscle AMPK during exercise/muscle contractions we hypothesized that AMPK may be the molecular switch communicates exercise intensity to other parts of the body. In this presentation we will discuss recent findings linking skeletal muscle AMPK with the control of insulin sensitivity and systemic energy metabolism.