5'AMP-activated protein kinase (AMPK) is recognised as an important intracellular energy sensor; shutting down energy consuming processes and turning on energy generating processes. Discovery of target proteins of AMPK has dramatically increased in the past 10 years. Historically, AMPK was first shown to regulate fatty acid and cholesterol synthesis, but is now hypothesised to take part in the regulation of energy/fuel balance not only at the cellular level but also at the level of the whole organism. In transgenic or knockout mouse models in which AMPK expression has been manipulated, exercise capacity is severely decreased. However, although AMPK may be required for fiber type switching in response to chronic exercise training, mitochondrial proteins increase similarly in AMPK deficient mice compared with wild type mice in response to exercise training. Thus, AMPK appears to play an important role in maintaining energy homeostasis during exercise but may not be required in order to adapt to exercise training; at least at the mitochondrial level. The mechanism by which exercise or muscle contraction signals to increase transport of glucose into skeletal muscle is not fully understood. Although some in vitro type studies suggest a role for AMPK in this regard other experiments performed in vivo show conflicting results. However, recently the TBC domain- containing proteins, TBC1D1 and TBC1D4, have been shown to be functional Rab GTPase activating proteins (Rab-GAPs) and to be both AMPK and Akt/PKB targets involved in the translocation of GLUT4 containing vesicles. Understanding the role of AMPK in regard to regulation of TBC1D1 and TBC1D4 Rab-GAP activity will be important in order to unravel these signalling pathways.