Activation of AMP-activated kinase (AMPK) suppresses NF-kappaB-mediated transcription in endothelial cells exposed to palmitate or TNF-alpha; it also impedes angiotensin II-driven proliferation in vascular smooth muscle cells. These phenomena become predictable if we postulate that AMPK can inhibit activation of NADPH oxidase. Such an effect would make sense from a homeostatic perspective, and moreover there is direct evidence that AMPK suppresses NADPH oxidase activation in neutrophils. New evidence that sub-pathological levels of peroxynitrite can activate AMPK suggest that this enzyme may act as an "early warning signal" for oxidant stress; inhibiting NADPH oxidase would constitute a rational feedback response to such a signal.