The AMP-activated protein kinase (AMPK) is the critical component of a highly conserved signalling pathway found in all eukaryotes that plays a key role in regulating metabolic processes in response to variations in energy supply and demand. AMPK protects cells from stresses that decrease cellular energy charge (i.e increase the AMP:ATP ratio) by initiating a shift in metabolism towards the generation of ATP while simultaneously down regulating pathways that consume ATP. The role of AMPK as an energy sensor extends beyond the cell and it is now apparent that it is a key regulator of whole-body energy homeostasis. These functions have stimulated considerable interest in AMPK as a promising target to treat metabolic disorders such as obesity and Type 2 diabetes. Recently, crystal structures of heterotrimeric core fragments and individual domains of AMPK from mammals, Schizosaccharomyces pombe and Saccharomyces cerevisiae have been solved. Together they provide an impressive insight into the molecular interactions involved in regulating kinase activity, heterotrimeric assembly, glycogen binding, and binding of the regulatory nucleotides AMP and ATP.