Maintaining energy balance is a key process at both the level of the individual cell and the whole body. In mammals, defects in energy homeostasis underlie the development of metabolic diseases, including type 2 diabetes and obesity, the incidence of which is increasing at a significant rate in humans. Understanding the molecular basis for energy balance is a prerequisite for developing new strategies, including pharmacological intervention, for combating the rise in these metabolic diseases. An important component in the regulation of energy homeostasis that has emerged over the last few years is the AMP-activated protein kinase (AMPK) 6 pathway. AMPK is a heterotrimeric protein kinase complex that acts as an energy sensor, responding to a rise in AMP levels by increasing ATP-generating pathways and reducing ATP-consuming pathways (1-3). Initially, AMPK was considered primarily as a gauge of energy status at the cellular level (4), and consistent with this idea, orthologues of AMPK have been identified in single cell eukaryotes, such as Saccharomyces cerevisiae (1). Accumulating evidence indicates, however, that in mammals AMPK regulates whole body energy homeostasis acting in metabolic tissues in response to nutrient and hormonal signals. For instance, the adipokines leptin and adiponectin activate AMPK stimulating fatty acid oxidation in liver and muscle (5, 6), while suppressing hepatic glucose production (6, 7). In addition to its peripheral effects, AMPK has been implicated in the central control of energy balance. Activation of AMPK in the hypothalamus has been reported to stimulate food intake, whereas inhibition leads to reduced food intake (8 -11). However, a recent study has reported that in mice a genetic deletion of AMPK in pro-opiomelanocortin neurons leads to an obese phenotype (12), conflicting with the results of previous studies.Many of the downstream effects of AMPK are predicted to be beneficial in treating, and potentially preventing, aspects of metabolic diseases. Consistent with this hypothesis, 5-aminoimidazole-4-carboxamide riboside, a compound that results in activation of AMPK in cells and in vivo, improved insulin sensitivity in animal models of insulin resistance (13-15). Furthermore, metformin, which has been used for nearly 50 years as an anti-diabetic drug and is currently estimated to be used by over 120 million people, activates AMPK via an indirect mechanism (16). It was reported recently that the glucose lowering effect of metformin requires hepatic expression of LKB1, an upstream kinase in the AMPK pathway, providing further evidence that in liver metformin acts via activation of AMPK (17). Taken together, these results indicate that activation of AMPK may provide an effective means for treatment of metabolic disorders.