Zinc oxide (ZnO) nanoparticle is added in various materials and products such as paints, plastics, ceramics, glass, rubber, pigments and sunscreen. Especially, ZnO nanoparticles are widely used in UV protection, because of their property of absorption ultraviolet light. Despite the widespread use of ZnO nanoparticles, there are many unknowns in understanding on their nanotoxicity and mechanisms. In this study, we evaluated the effects of ZnO nanoparticles on gene expression pattern of human keratinocyte cells. Total RNA was prepared from the exposure groups to ZnO nanoparticles with different surface charge, and cDNA microarray was performed using Agilent human whole genome array. Our study indicated that genes related to apoptosis and response to stress including heme oxygenase 1 (HMOX1), superoxide dismutase (SOD), glutathione peroxidase (GPX), BNIP3L (adenovirus E1B 19 kDa interacting protein 3) and heat shock 70 kDa protein (HSP70) were up- and down-regulated in ZnO nanoparticles treated cells. Moreover, our results showed that ZnO nanoparticles induced intracellular reactive oxygen species (ROS) and oxidative stress. Antioxidant enzyme SOD levels were significantly higher and GSH levels were decreased in ZnO nanoparticles-exposed cells, respectively. The present study showed that up-regulation of these genes by ZnO nanoparticles could increase the production of ROS and oxidative stress. Therefore, ZnO nanoparticles could have a potential to product ROS through the perturbation of metabolic pathway, inducing oxidative stress. It also supported that the nanotoxicity mechanism could correlate with the active oxygen production, oxidative stress, apoptosis, and antioxidant defense mechanisms.