The brain developed adaptive mechanisms in the face of changing environments and stresses imposed on the nervous system. The addition of glutamate as the major excitatory amino acid neurotransmitter to the brain's complement of amino acids and peptides dictated a coordinated transcriptional and translational program to meet the demands of excitatory neurotransmission. One such program is the ability of neurons to sustain and maintain their survival given the nature of glutamate-mediated receptor activation. The unique development of endogenous neuronal pathways activated by glutamate receptors transformed neurons and allowed them to survive under conditions of high energy demands. These same endogenous survival pathways also mediate plastic responses to meet another demand of the brain, adaptation. An endogenous protein that plays a central role in glutamate receptor-mediated survival pathways is brain-derived neurotrophic factor (BDNF). Intermittent but frequent synaptic ionotropic glutamate receptor activation ensures neuronal survival through a BDNF autocrine loop. In sharp contrast, overactivation of ionotropic glutamate receptors leads to neuronal cell death. Thus, innovative strategies that induce endogenous neuronal survival pathways through low-level activation of ionotropic glutamate receptors or those that bypass receptor activation but upregulate endogenous survival pathways may not only prevent neurodegenerative disorders that involve glutamate as a final common pathway that kills neurons, but may also provide treatment alternatives critical for neurons to survive stressful conditions such as stroke, status epilepticus and hypoglycemic-induced neuronal cell death.