There is growing concern about the safety of engineered nanoparticles, which are produced for various industrial applications. Quantum dots are colloidal semiconductor nanoparticles that have unique luminescence characteristics and the potential to become attractive tools for medical imaging. However, some of these particles can cause oxidative stress and induce cell death. The objective of this study was to explore quantum dot-induced metabolic changes, which could occur without any apparent cellular damage. We provide evidence that both uncoated and ZnS-coated quantum dots can induce the accumulation of lipids (increase in cytoplasmic lipid droplet formation) in two cell culture models: glial cells in primary mouse hypothalamic cultures and rat pheochromocytoma PC12 cells. Glial cells treated with CdTe quantum dots accumulated newly synthesized lipids in a phosphoinositide 3-kinase-dependent manner, which was consistent with the growth factor-dependent accumulation of lipids in PC12 cells treated with CdTe and CdSe/ZnS quantum dots. In PC12 cells, quantum dots, as well as the hypoxia mimetic CoCl(2), induced the up-regulation of hypoxia-inducible transcription factor-1alpha and the down-regulation of the beta-oxidation of fatty acids, both of which could contribute to the accumulation of lipids. On the basis of our results, we propose a model illustrating how nanoparticles, such as quantum dots, could trigger the formation of intracellular lipid droplets, and we suggest that metabolic measurements, such as the determination of fat oxidation in tissues, which are known sites of nanoparticle accumulation, could provide useful measures of nanoparticle safety. Such assays would expand the current platform of tests for the determination of the biocompatibility of nanomaterials.