Heat shock factor 1 (HSF1) mediates the cellular response to stress to increase the production of heat shock protein (HSP) chaperones for proper protein folding, trafficking, and degradation; failure of this homeostatic mechanism likely contributes to neurodegeneration. We show that the neuroprotective drug riluzole increased the amount of HSF1 in NG108-15 neuroprogenitor cells by slowing the specific turnover of HSF1 and supporting a more robust and sustained activation of HSF1. Using Hsp70-luciferase as a functional readout of the activity of HSF1, we show that riluzole amplified the heat shock induction of the reporter gene with an optimal increase at 1 M. Immunocytochemical staining and Western blot quantitation of HSP70 in NG108-15 neuroprogenitor cells and embryonic spinal cord neurons provided corroborative evidence that riluzole amplified the HSF1-dependent regulation of HSP70 expression. Parallel studies on the GLT1 glutamate transporter showed that riluzole increased GLT1-reporter and GLT1 protein expression and that the increase was enhanced by heat shock and coincident with the increased expression of HSP70 and HSP90. This result is consistent with the anti-glutamatergic profile of riluzole and the presence of multiple heat shock elements on the GLT1 gene promoter, suggesting that riluzole may modulate GLT1 expression through HSF1. The increased HSP chaperones and GLT1 transporter blunted glutamate-induced and N-methyl D-aspartate receptor-mediated excitotoxic death. In summary, we show that riluzole increased the amount and activity of HSF1 to boost the expression of HSPs and GLT1 for neuroprotection under stress.Induction of the heat shock response (HSR 2 ; also known as stress response) is a universally important quality control mechanism in protein homeostasis; it is a primary and evolutionarily conserved response to diverse stressors, mediated by activation of the HSF1 transcription factor, culminating in the induction of a family of heat shock proteins (HSPs) that function as chaperones to assist in the proper folding of non-native proteins and proteases to help in the degradation of damaged proteins for the protection and recovery from cellular damages (1-3). The biological importance of HSR is underscored by genetic evidence linking stress and protein homeostasis with the health and life span of the organism (4 -6) and by the increasing appreciation that problems in protein folding and aggregation likely contribute to the pathogenesis of a number of age-dependent neurodegenerative diseases that include amyotrophic lateral sclerosis (ALS), Huntington, Parkinson, Alzheimer, and prion diseases (6 -10).We are interested in harnessing the cytoprotective activity of HSR/HSF1 to promote cell survival under stress. In particular, we are interested in identifying agents that are not overtly proteotoxic and would not by themselves induce a robust HSR but would amplify the HSR and enhance the expression of HSPs. Riluzole is the only Food and Drug Administration-approved drug for ALS. The mode of action ...