The movement of neutral amino acids across the blood-brain barrier is bidirectional, however, blood to brain transport is much better characterized than brain to blood transport. Available evidence points to the existence of a single transport system (system L) at the luminal capillary surface. The properties of this system place constraints on possible mechanisms of regulating blood-brain neutral amino acid transport activity. One property, mediation of exchange transport, suggests that amino acid influx is coupled to efflux, particularly efflux of glutamine, synthesized in glial astrocytes from ammonia and glutamic acid. Such a coupling could account for increased blood-brain neutral amino acid transport in liver disease and decreased transport activity after treatment with methionine sulfoximine, a glutamine synthetase inhibitor.