AMP-activated protein kinase (AMPK) is a widely conserved Ser/Thr-specific protein kinase, homologous to Saccharomyces cerevisiae Snf1, and involved in nutrient sensing in lower organisms. In 2003, we reviewed the role of this enzyme in glucose homeostasis in mammals [Rutter, G.A., daSilvaXavier, G., Leclerc, I., 2003. Roles of 5'-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem. J. 375 (Pt 1), 1-16]. In the subsequent 5 years, dramatic strides have taken place in our understanding of the role of AMPK in the control of whole body metabolic homeostasis, the regulation of the enzyme by upstream kinases, and its molecular structure. These new studies and earlier work arguably propel AMPK, and perhaps related family members into a "super league" of potential therapeutic targets for maladies including diabetes, cancer, heart disease, and obesity. Here, we survey some of these recent advances, focussing on the role of this and related enzymes in the control of pancreatic beta-cell function and glucose homeostasis.