The staggering array of nanotechnological products, found in our environment and those applicable in medicine, has stimulated a growing interest in examining their long-term impact on genetic and epigenetic processes. We examined here the epigenomic and genotoxic response to cadmium telluride quantum dots (QDs) in human breast carcinoma cells. QD treatment induced global hypoacetylation implying a global epigenomic response. The ubiquitous responder to genotoxic stress, p53, was activated by QD challenge resulting in translocation of p53, with subsequent upregulation of downstream targets Puma and Noxa. Consequential decrease in cell viability was in part prevented by the p53 inhibitor pifithrin-alpha, suggesting that p53 translocation contributes to QD-induced cytotoxicity. These findings suggest three levels of nanoparticle-induced cellular changes: non-genomic, genomic and epigenetic. Epigenetic changes may have long-term effects on gene expression programming long after the initial signal has been removed, and if these changes remain undetected, it could lead to long-term untoward effects in biological systems. These studies suggest that aside from genotoxic effects, nanoparticles could cause more subtle epigenetic changes which merit thorough examination of environmental nanoparticles and novel candidate nanomaterials for medical applications.