A single entity, the AMP‐activated protein kinase (AMPK), phosphorylates and regulates in vivo hydroxymethylglutraryl‐CoA reductase and acetyl‐CoA carboxylase (key regulatory enzymes of sterol synthesis and fatty acid synthesis, respectively), and probably many additional targets. The kinase is activated by high AMP and low ATP via a complex mechanism, which involves allosteric regulation, promotion of phosphorylation by an upstream protein kinase (AMPK kinase), and inhibition of dephosphorylation. This protein‐kinase cascade represents a sensitive system, which is activated by cellular stresses that deplete ATP, and thus acts like a cellular fuel gauge. Our central hypothesis is that, when it detects a ‘low‐fuel’ situation, it protects the cell by switching off ATP‐consuming pathways (e.g. fatty acid synthesis and sterol synthesis) and switching on alternative pathways for ATP generation (e.g. fatty acid oxidation). Native AMP‐activated protein kinase is a heterotrimer consisting of a catalytic α subunit, and β and γ subunits, which are also essential for activity. All three subunits have homologues in budding yeast, which are components of the SNF1 protein‐kinase complex. SNF1 is activated by glucose starvation (which in yeast leads to ATP depletion) and genetic studies have shown that it is involved in derepression of glucose‐repressed genes. This raises the intriguing possibility that AMPK may regulate gene expression in mammals. AMPK/SNF1 homologues are found in higher plants, and this protein‐kinase cascade appears to be an ancient system which evolved to protect cells against the effects of nutritional or environmental stress.