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Skeletal muscle insulin resistance is a hallmark feature of Type 2 diabetes. Physical exercise/muscle contraction elicits an insulin-independent increase in glucose transport and perturbation of this pathway may bypass defective insulin signaling. To date, the exercise-responsive signaling molecules governing glucose metabolism in skeletal muscle are largely unknown. AMPactivated protein kinase (AMPK) has been suggested as one of the exercise-responsive signaling molecules involved in glucose homeostasis and consequently it has been heavily explored as a pharmacological target for the treatment of Type 2 diabetes. AMPK exists in heterotrimeric complexes composed of a catalytic α-subunit and regulatory β- and γ-subunits. The γ3-isoform of AMPK is expressed specifically in skeletal muscle of humans and rodents and this tissue specific expression pattern offers selectivity in AMPK action. Furthermore, mutations in the AMPK γ3-isoform may provide protection from diet-induced insulin resistance by increasing lipid oxidation in the presence of increased lipid supply. This review highlights the current understanding of the role of the regulatory AMPK γ3-isoform in the control of skeletal muscle metabolism.