The acidic amino acid glutamate activates a family of ligand-gated ion channels to mediate depolarization that can be as short-lived as a few milliseconds and activates a family of G protein-coupled receptors that couple to both ion channels and other second messenger pathways. Glutamate is the predominant excitatory neurotransmitter in the mammalian central nervous system and is required for essentially all motor, sensory, and cognitive functions. In addition, glutamate-mediated signaling is required for development and the synaptic plasticity thought to underlie memory formation and retrieval. The levels of glutamate in brain approach 10 mmol/kg and most cells in the CNS express at least one of the receptor subtypes. Unlike acetylcholine that mediates "rapid" excitatory neurotransmission at the neuromuscular junction, there is no evidence for extracellular inactivation of glutamate. Instead, glutamate is cleared by a family of Na(+)-dependent transport systems that are found on glial processes that sheath the synapse and found on the pre- and postsynaptic elements of neurons. These transporters ensure crisp excitatory transmission by maintaining synaptic concentrations below those required for tonic activation of glutamate receptors under baseline conditions (approximately 1 microM) and serve to limit activation of glutamate receptors after release. During the past few years, it has become clear that like many of the other neurotransmitter transporters discussed in this volume of Handbook of Experimental Pharmacology, the activity of these transporters can be rapidly regulated by a variety of effectors. In this chapter, a broad overview of excitatory signaling will be followed by a brief introduction to the family of Na(+)-dependent glutamate transporters and a detailed discussion of our current understanding of the mechanisms that control transporter activity. The focus will be on our current understanding of the mechanisms that could regulate transporter activity within minutes, implying that this regulation is independent of transcriptional or translational control mechanisms. The glutamate transporters found in forebrain are regulated by redistributing the proteins to or from the plasma membrane; the signals involved and the net effects on transporter activity are being defined. In addition, there is evidence to suggest that the intrinsic activity of these transporters is also regulated by mechanisms that are independent of transporter redistribution; less is known about these events. As this field progresses, it should be possible to determine how this regulation affects physiologic and pathologic events in the CNS.