AMPK is present in all tissues as an αβγ heterotrimer, and its expression is regulated by multiple genes encoding each of the subunits (α1, α2, β1, β2, γ1, γ2, γ3) with differential tissue-specific expression and activity. AMPK regulates cellular energy metabolism through direct effects on gene transcription and key metabolic enzymes. This typically occurs at multiple points in metabolic pathways as is illustrated by AMPK's regulation of lipid metabolism. At the whole body level, AMPK helps control appetite, energy expenditure, and substrate utilization in response to exercise, nutrients, and cytokines and may be linked to many physiological processes. AMPK has now fully emerged from its historical orphan status as a cellular metabolic stress sensor to a highly integrated signaling junction for many biochemical pathways. Nevertheless, despite AMPK's ascent to “super metabolic regulator” status, it is becoming increasingly clear AMPK is just one of a number of players. Indeed, AMPK can suffer from the “Heisenberg uncertainty” phenomenon where the harder you look the less it seems to be essential, as appears to be the case for AMPK's role in exercise-induced glucose uptake. AMPK signaling may be altered in a number of disease conditions; however, despite the convincing associations between AMPK signaling under a number of different conditions and treatments, there is nevertheless an urgent need for studies using genetic models of AMPK deficiency/functional titration to fully evaluate the quantitative role of AMPK in regulating physiological responses in vivo. We can look forward to an exciting vista of future discoveries that answer the following pressing questions: how significant is AMPK to the etiology of type 2 diabetes? Will future drug development lead to a repetoire of β1 and β2 specific antagonists and agonists? Will AMPK targeted therapy have a role in obesity treatment? Is AMPK a practical target for cancer therapy? Can AMPK-activating drugs mimic the beneficial metabolic effects of diet and exercise? Can AMPK therapy improve the quality of life in the elderly