The AMP-activated protein kinase (AMPK) system is a key regulator of energy balance. AMPKs are heterotrimeric complexes composed of a catalytic alpha subunit and regulatory beta and gamma subunits. Any metabolic stress that increases ATP consumption (e.g. muscle contraction) or that inhibits ATP production (e.g. hypoxia, glucose deprivation, or mitochondrial inhibitors) will cause a fall in the ATP:ADP ratio, which is amplified by adenylate kinase into a much larger rise in the AMP:ATP ratio. Binding of AMP to two tandem “Bateman domains” on the gamma subunit of AMPK causes activation of the kinase, an effect antagonized by high concentrations of ATP. Intriguingly, point mutations in the Bateman domains of the gamma-2 isoform that interfere with binding of AMP and ATP cause heart disease associated with excessive storage of glycogen. AMPK is only active after phosphorylation of a conserved threonine within the kinase domain (Thr-172 in the human) by upstream kinases. The principal upstream kinase in mammals is the tumour suppressor, LKB1, in complex with two accessory subunits, STRAD and MO25. The LKB1 complex appears to phosphorylate AMPK at Thr-172 constitutively, but in basal conditions the phosphate is immediately removed by phosphatases, most likely forms of protein phosphatase-2C. Binding of AMP to the Bateman domain inhibits dephosphorylation of Thr-172, thus switching the kinase into the active, phosphorylated form. In mammals, the phosphorylated kinase is also allosterically activated by AMP. We have recently shown [1] that AMP binding relieves inhibition of the kinase domain by a pseudosubstrate sequence that occurs within the N-terminal Bateman domain on the gamma subunit. In certain cells such as neurones, endothelial cells and T lymphocytes, AMPK can also be activated by a rise in cytosolic calcium, which binds to calmodulin and triggers phosphorylation of Thr-172 by calmodulin-dependent protein kinase kinase-beta. This can occur in the absence of an increase in AMP, and may represent a mechanism to anticipate the demand for ATP that often accompanies elevation of cell calcium. Once activated, AMPK switches on catabolic processes such as the uptake and oxidation of glucose and fatty acids, and mitochondrial biogenesis. Conversely, it switches off anabolic processes such as fatty acid and cholesterol synthesis, gluconeogenesis, and glycogen and protein synthesis. It achieves these effects both by direct phosphorylation of metabolic enzymes and via phosphorylation of transcription factors and co-activators that regulate gene expression. In proliferating cells, AMPK activation also inhibits cell growth by inhibition of the mTOR pathway, as well as progress through the cell cycle. AMPK appears to be an ancient system that evolved in single-celled eukaryotes to mediate the response to starvation for a carbon source. However, it has recently become clear that its role became adapted during development of multicellular organisms, where it is also involved in the regulation of energy balance at the whole body level. Thus, in muscle AMPK is activated by adipokines and cytokines such as leptin, adiponectin and interleukin-6, where it increases energy expenditure by stimulating glucose and fatty acid oxidation. In the liver, AMPK is activated by adiponectin, stimulating fatty acid oxidation and repressing the expression of enzymes of gluconeogenesis. Finally, in the hypothalamus it is modulated by agents that regulate appetite and food intake, being inhibited by leptin, and activated by ghrelin, cannabinoids and hypoglycaemia. Activation of AMPK in the hypothalamus also increases food intake in rodents. Thus, a system that appears to have evolved for the response to starvation in single-celled eukaryotes now controls a complex behavioural response in multicellular eukaryotes, i.e. feeding. Given the downstream effects of AMPK, i.e. its ability to stimulate oxidation of glucose and fatty acids in the periphery, and to repress synthesis of lipids and glucose in the liver, activators of the kinase have great potential as drugs to treat type 2 diabetes and the metabolic syndrome, and possibly even obesity [2]. Consistent with this, AMPK appears to be the therapeutic target of metformin, a drug now used to treat 120 million people with type 2 diabetes worldwide. However, metformin activates AMPK indirectly by acting as a mitochondrial inhibitor, and it is possible that a direct activator could be more efficacious and/or have fewer side effects. AMPK is also activated physiologically by exercise, not only in skeletal and cardiac muscle but also in liver and adipose tissue, and it seem likely that it is responsible for many of the beneficial effects of regular exercise, particularly in protection against the development of obesity and type 2 diabetes.