Abstractl‐glutamate is the predominant excitatory neurotransmitter in theCNSand has a central role in a variety of brain functions. The termination of glutamate neurotransmission by excitatory amino acid transporters (EAATs) is essential to maintain glutamate concentration low in extracellular space and avoid excitotoxicity.EAAT2/GLT‐1, being the most abundant subtype of glutamate transporter in theCNS, plays a key role in regulation of glutamate transmission. Dysfunction ofEAAT2 has been correlated with various pathologies such as traumatic brain injury, stroke, amyotrophic lateral sclerosis, Alzheimer's disease, among others. Therefore, activators of the function or enhancers of the expression ofEAAT2/GLT‐1 could serve as a potential therapy for these conditions. Translational activators ofEAAT2/GLT‐1, such as ceftriaxone andLDN/OSU‐0212320, have been described to have significant protective effects in animal models of amyotrophic lateral sclerosis and epilepsy. In addition, pharmacological activators of the activity ofEAAT2/GLT‐1 have been explored for decades and are currently emerging as promising tools for neuroprotection, having potential advantages over expression activators. This review describes the current status of the search forEAAT2/GLT‐1 activators and addresses challenges and limitations that this approach might encounter.imageTermination of glutamate neurotransmission by glutamate transporter EAAT2 is essential to maintain homeostasis in the brain and to avoid excitotoxicity. Dysfunction of EAAT2 has been correlated with various neurological pathologies. Therefore, activators of the function or enhancers of the expression of EAAT2 (green arrows) could serve as a potential therapy for these conditions. This review describes the current status of the search for EAAT2 activators and addresses challenges and limitations of this approach.