Despite the myriad applications of nanoparticles and possible high human exposure, the impact of manufactured nanoparticles on the environment and human health is not clear. Most studies on the biological effects of nanoparticles focused on the activities of functional components, such as drugs, proteins, antibodies, etc., conjugated to the nanoparticles. More recently, some naked nanoparticles were found to be cytotoxic and affect cellular activities. Envirox, a trade name for naked cerium oxide (CeO2) nanoparticle used as a diesel fuel additive, has been demonstrated to reduce fuel consumption and the emission of carbon dioxide and particulate from vehicles. However the health impact of CeO2 nanoparticles is poorly understood. To generate a detailed, unbiased assessment of the molecular responses to CeO2 nanoparticles (CeO-6, 6 nm), we conducted a genomic study to identify gene expression signatures associated with nanoparticle exposure in a murine neuronal cell (HT22) model. We controlled for the effect of particle size using 1000 nm diameter cerium oxide (CeO-M) and for the effect of chemical property using 300 nm diameter aluminum oxide particles (AlO). We demonstrated cerium oxide nanoparticles induced chemical- and size-specific changes in the transcriptome of murine neuronal cells. The genes whose expression is affected by the presence of CeO-6 are related to neurological disease, cell cycle control and growth. On the other hand, similar studies with human mesenchymal stem cells revealed the induction of osteogenic factors by CeO-6. These observations indicate that nanoparticles are capable of inducing size- and chemistry-specific changes in cells and caution the use and need for in-depth assessment of potential health risks of nanoparticle exposure.