The evolutionarily conserved serine/threonine kinase, AMP-activated protein kinase (AMPK), functions as a cellular fuel gauge that regulates metabolic pathways in glucose and fatty acid metabolism and protein synthesis. Recent data strongly implicate the AMPK–acetyl CoA carboxylase (ACC)–malonyl CoA pathway in the hypothalamus in the regulation of food intake, body weight and hepatic glucose production. Furthermore, data indicate that AMPK is a mediator of the effects of adipocyte-derived and gut-derived hormones and peptides on fatty acid oxidation and glucose uptake in peripheral tissues. Studies are now elucidating the potential role of kinases upstream of AMPK in these metabolic effects. In addition, recently, several novel downstream effectors of AMPK have been identified. The AMPK pathway in the hypothalamus and peripheral tissues coordinately integrates inputs from multiple hormones, peptides and nutrients to maintain energy homeostasis.