In 1977 I got the opportunity to start my own laboratory at the University of Dundee, with the help of my mentor Philip Cohen. The first decision was what I would work on. At the time the only process definitively known to be regulated by protein phosphorylation was glycogen metabolism (which Philip worked on) and I was keen to study the role of this covalent modification in some other pathway. One evening Philip and I went to a local pub with copies of three or four papers, each presenting preliminary evidence that other pathways might be regulated by phosphorylation. After two beers I had (rather arbitrarily!) decided to follow up a paper by Ki-han Kim at Purdue University, which suggested that acetyl-CoA carboxylase (a key regulatory enzyme of fatty acid synthesis) was inactivated by a then poorly defined protein kinase. During my talk I will describe the experiments that led to the realization that this kinase, which we renamed AMP-activated protein kinase, was activated both by AMP and by phosphorylation by upstream kinase(s), and that it phosphorylated and inactivated not only acetyl-CoA carboxylase but also HMG-CoA reductase, which is involved in cholesterol synthesis. I will also describe a subsequent series of exciting experiments in which we and others defined the upstream kinases. Finally, I will describe recent studies, which: (1) help to clarify the role of ADP in regulation of AMPK; (2) suggest that AMPK inhibitors might be useful in treatment of some cancers, and (3) investigate a new inhibitor.