Glutamate (Glu) is the major excitatory neurotransmitter in the vertebrate central nervous system. During synaptic activity, Glu is released into the synaptic cleft and binds to Glu receptors activating a wide variety of signal transduction cascades. Extracellular Glu concentrations are maintained exclusively within physiological levels mainly by glial Glu transporters. Inefficient clearance of synaptic Glu may be neurotoxic owing to prolonged hyperactivation of postsynaptic Glu receptors, causing a multitude of intracellular events in the postsynaptic neuron, which ultimately results in neuronal cell death. This phenomenon is known as excitotoxicity and is the underlying mechanisms of a number of neurodegenerative diseases. Therefore, it is important to understand the regulation of Glu transporters' function. Transporter activity can be regulated in different ways, including gene expression, transporter protein targeting and trafficking, and posttranslational modifications of the transporter protein. The identification of these mechanisms has allowed to understand the role of Glu transporters during pathology and will aid in the development of therapeutic strategies for treating or preventing pathologies associated with excitotoxicity.