AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is expressed in most mammalian tissues including cardiac muscle. Among the multiple biological processes influenced by AMPK, regulation of fuel supply and energy-generating pathways in response to the metabolic needs of the organism is fundamental and likely accounts for the remarkable evolutionary conservation of this enzyme complex. By regulating the activity of acetyl–coenzyme A carboxylase, AMPK affects levels of malonyl–coenzyme A, a key energy regulator in the cell. AMPK is generally quiescent under normal conditions but is activated in response to hormonal signals and stresses sufficient to produce an increase in AMP/ATP ratio, such as hypoglycemia, strenuous exercise, anoxia, and ischemia. Once active, muscle AMPK enhances uptake and oxidative metabolism of fatty acids as well as increases glucose transport and glycolysis. Data from AMPK deficiency models suggest that AMPK activity might influence the pathophysiology and therapy of diabetes and increase heart tolerance to ischemia. Effects that are not as well understood include AMPK regulation of transcription. Different AMPK isoforms are found in distinct locations within the cell and have distinct functions in different tissues. A principal mode of AMPK activation is phosphorylation by upstream kinases (eg, LKB1). These kinases have a fundamental role in cell-cycle regulation and protein synthesis, suggesting involvement in a number of human disorders including cardiac hypertrophy, apoptosis, cancer, and atherosclerosis. The physiological role played by AMPK during health and disease is far from being clearly defined. Naturally occurring mutations affecting the nucleotide-sensing modules in the regulatory γ subunit of AMPK lead to enzyme dysregulation and inappropriate activation under resting conditions. Glycogen accumulation ensues, leading to human disease manifesting as cardiac hypertrophy, accessory atrioventricular connections, and degeneration of the physiological conduction system. Whether AMPK is a key participant or bystander in other disease states and whether its selective manipulation may significantly benefit these conditions remain important questions.