Fuel metabolism is highly regulated to ensure adequate energy for cellular function. The contribution of the major metabolic fuels--glucose, lactate and fatty acids (FAs)--often reflects their circulating levels. In addition, regulatory cross-talk and fuel-induced hormone secretion ensures appropriate and co-ordinate fuel utilization. Because its activity can either determine or reflect fuel preference (carbohydrate versus fat), the pyruvate dehydrogenase complex (PDC) occupies a pivotal position in fuel cross-talk. Active PDC permits glucose oxidation and allows the formation of mitochondrially derived intermediates (e.g. malonyl-CoA and citrate) that reflect fuel abundance. FA oxidation suppresses PDC activity. PDC inactivation by phosphorylation is catalysed by pyruvate dehydrogenase kinases (PDKs) 1-4, which are regulated differentially by metabolite effectors. Most tissues contain at least two and often three of the PDK isoforms. We develop the hypothesis that PDK4 is a "lipid status"-responsive PDK isoform facilitating FA oxidation and signalling through citrate formation. Substrate interactions at the level of gene transcription extend glucose-FA interactions to the longer term. We discuss potential targets for substrate-mediated transcriptional regulation in relation to selective PDK isoform expression and the influence of altered PDK isoform expression in fuel sensing, selection and utilization.