Glutamate is the primary excitatory amino acid neurotransmitter in the central nervous system and its activity is carefully modulated in the synaptic cleft by glutamate transporters. A number of glutamate transporters have been identified in the central nervous system and each has a unique physiologic property and distribution. Glutamate transporter dysfunction may either be an initiating event or part of a cascade leading to cellular dysfunction and ultimately cell death. Animal models of glutamate transporter dysfunction have revealed a significant role for these proteins in pathologic conditions such as neurodegenerative diseases, epilepsy, stroke, and central nervous system tumors. Recent work has focused on glutamate transporter biology in human diseases with an emphasis on how manipulation of these transporter proteins may lead to therapeutic interventions in neurologic disease.