Cellular adaptation is the dynamic response of a cell to adverse changes in its intra/extra cellular environment. The aims of this study were to investigate the role of: (i) the glutathione antioxidant system, and (ii) the transcription factor EB (TFEB), a newly revealed master regulator of lysosome biogenesis, in cellular adaptation to nanoparticle-induced oxidative stress. Intracellular concentrations of glutathione species and activation of TFEB were assessed in rat pheochromocytoma (PC12) cells following treatment with uncapped CdTe quantum dots (QDs), using biochemical, live cell fluorescence and immunocytochemical techniques. Exposure to toxic concentrations of QDs resulted in a significant enhancement of intracellular glutathione concentrations, redistribution of glutathione species and a progressive translocation and activation of TFEB. These changes were associated with an enlargement of the cellular lysosomal compartment. Together, these processes appear to have an adaptive character, and thereby participate in the adaptive cellular response to toxic nanoparticles.