AMP-activated protein kinase (AMPK) activity responds to a requirement to increase cellular ATP production and/or to conserve available ATP. AMPK is therefore central to the mechanisms of adjustment to fluctuating energy demand or metabolic substrate supply. AMPK has important actions in several insulin-responsive tissues, as well as in the pancreatic β cell, through which it can modulate glycemic control, insulin action and metabolic substrate selection and disposal. We review recent novel findings elucidating the mechanisms by which AMPK activation can correct impaired insulin action. However, we also emphasize not only the similarities, but also the differences in the actions of insulin and AMPK. We focus on metabolic interfaces between AMPK, peroxisomal proliferator-activated receptors, sirtuins and mTORC.