The 5'-adenosine monophosphate-activated protein kinase (AMPK) is a metabolic and stress sensor that has been functionally conserved throughout eukaryotic evolution. Activation of the AMPK system by various physiological or pathological stimuli that deplete cellular energy levels promotes activation of energy restorative processes and inhibits energy consumptive processes. AMPK has a prominent role not only as a peripheral sensor of energy balance, but also in the CNS as a multifunctional metabolic sensor. Recent work suggests that AMPK plays an important role in maintaining whole body energy balance by coordinating feeding behaviour through the hypothalamus in conjunction with peripheral energy expenditure. In addition, brain AMPK is activated by energy-poor conditions induced by hypoxia, starvation, and ischaemic stroke. Under these conditions, AMPK is activated as a protective response in an attempt to restore cellular homeostasis. However in vivo, it appears that the overall consequence of activation of AMPK is more complex than previously imagined, in that over-activation may be deleterious rather than neuroprotective. This review discusses recent findings that support the role of AMPK in brain as a multidimensional energy sensor and the consequences of its activation or inhibition under physiological and pathological states.