AMP-activated protein kinase (AMPK) acts as a cellular energy sensor, with orthologues in all eukaryotic kingdoms, including protozoa, fungi and plants. AMPK is only active after phosphorylation at T172 within the catalytic subunit by upstream kinases, the most important of which is LKB1, which provides a continual basal phosphorylation. The ligand that activates the kinase, AMP, is produced from ADP by adenylate kinase whenever the cellular ADP:ATP ratio rises, signalling a drop in cellular energy status. This causes replacement of ATP by AMP at two sites on the regulatory gamma subunit of AMPK, triggering a conformational change that inhibits dephosphorylation and switches the kinase to the active phosphorylated form. AMP binding also further activates the phosphorylated form. This dual mechanism provides a sensitive mechanism that causes a large rise in AMPK activity in response to a small fall in cellular energy status. AMPK is activated by stresses that interfere with ATP synthesis (e.g. hypoxia, hypoglycemia) or that accelerate ATP consumption. In some cells, including neurons and endothelial cells, AMPK can also be activated by a rise in cytosolic calcium ions, which activates the calmodulin-dependent kinase CaMKK-beta. leading to phosphorylation of T172 even without a rise in AMP. Once activated, AMPK phosphorylates numerous downstream targets that switch on catabolic pathways generating ATP, while switching off ATP-consuming anabolic processes. AMPK is switched on in muscle by contraction, and is responsible for many of the associated metabolic changes such as increase glucose uptake, fatty acid oxidation and mitochondrial biogenesis. AMPK is the target for the drug metformin, currently prescribed to 120 million patients with type 2 diabetes worldwide. Since LKB1 is known to be a tumour suppressor and AMPK activation inhibits cell growth and proliferation, metformin is currently being tested as an anti-cancer drug.