Variations of substrate transport across the cerebral capillary endothelium were examined in response to variations of the substrate demand of the brain tissue, and to variations of substrate concentration in the blood. The substrates examined included glucose and ketone bodies. The transport changes were measured in rats, using an indicator fractionation method modified by the reviewer. Four mechanisms appeared to contribute to the adjustment of substrate transport to variations in substrate demand. The first and least important mechanism was the change of concentration gradient across the endothelium that occurred when the substrate consumption rate changed. The second mechanism was the flow-dependency of the average capillary substrate concentration: the higher the perfusion rate, the higher the average capillary concentration. This mechanism failed to account for the changes of substrate transport observed during marked increases of the metabolic rate. The third and most important mechanism was a change of the capillary diffusion capacity, probably associated with a change of the number of perfused capillaries. The fourth mechanism, not previously described, was an adaptation of transport to permanent changes of substrate concentration in the blood. This mechanism appeared to reflect changes of the concentration (and affinity?) of transport proteins in the plasma membranes of endothelial cells, possibly in association with changes of cellular protein synthesis and gene expression.