Adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) is a key player in regulating energy metabolism, placing it at the center stage in studies of diabetes and related metabolic diseases. Expressed in key metabolically relevant organs, AMPK is activated in response to a variety of stimuli, including cellular stress, exercise, and a wide range of hormones and agents that exert impacts on cellular metabolism. Genetic and pharmacological studies demonstrate that AMPK is required for maintaining glucose homeostasis. Activation of AMPK by pharmacological agents presents a unique challenge, given the complexity of the biology, but holds a considerable potential to reverse the metabolic abnormalities associated with type 2 diabetes.