Intracellular sensors of cellular energy and nutrient status are emerging as key players in the regulation of cell metabolism in health and disease. AMP-activated protein kinase (AMPK) participates in the control of cellular and whole-body energy balance by its exquisite sensitivity to AMP. AMPK is thus able to sense and to react to an increasing AMP:ATP ratio within a complex upstream and downstream signaling network that responds to different energetic and metabolic stresses. The kinase forms heterotrimers with catalytic a-and regulatory b-, and g-subunits, which exist as different isoforms and splice variants. Global and local cellular ATP:ADP and phosphocreatine:creatine ratios are controlled by the reactions of adenylate kinase and creatine kinase, respectively, which are the first safeguards for keeping cellular ATP:ADP and ATP:AMP ratios high for as long aspossible. However, AMPK operates under different metabolic conditions, with different modes of operation and in subsequent time frames. AMP is present at sub-micromolar concentrations in resting cells and increases strongly as a result of the adenylate kinase reaction when ATP is depleted. It is thus an ideal second messenger for reporting cellular energy status to the sensor AMPK. Full activation of AMPK is more complex. In addition to allosteric stimulation by micromolar AMP concentrations, it involves both covalent activation and inhibition viachanges in phosphorylation of the Thr172 residue of the a-subunits by different upstream kinases and phosphatases. Such activation depends on different kinds of energy stress as well as on hormones and other signals, including changes in calcium. As a consequence, AMPK aims not only at cellular energy homeostasis but also at whole-body energy balance. Once activated, AMPK induces compensatory measures to maintain cellular ATP:ADP ratios for cell survival. It regulates a large number of downstream targets, shutting down anabolic pathways and stimulating catabolic pathways, thus simultaneously sparing limited energy resources and acquiring extra energy, respectively. AMPK acts at two control levels that are responsible for acute and chronic responses: first by directly affecting the activity of key enzymes, e.g., in glucose and fat metabolism, and second by longer-term transcriptional control of key players of these metabolic pathways. However, new evidence indicates that AMPK also participates in the control of non-metabolic processes such as cell proliferation and cell cycle. Lastly, the kinase complex has been proposed as a potential drug target in treatment of type II diabetes, because its activation both stimulates insulin-independent glucose uptake in the periphery and suppresses glucose production by the liver. More recently, the discovery of AMPK activation by the tumor suppressor LKB1 suggests a strong connection between metabolic signaling and cancer.