Cerium oxide nanoparticles (CNPs) have been recently studied for their potent superoxide scavenging properties in both cell and animal model systems. Data from these model systems have shown that exposure of cells to CNPs results in the protection against reactive oxygen species (ROS). Despite these exciting findings, very little is known regarding the uptake or subcellular distribution of these nanomaterials inside cells. In this study we utilized fluorophore (carboxyfluorescein) conjugated cerium oxide NPs (CCNPs) to study the mechanism of uptake and to elucidate the subcellular localization of CNPs using a keratinocyte model system. We observed rapid uptake (within 3 h) of CCNPs that was governed by energy-dependent, clathrin-mediated and caveolae-mediated endocytic pathways. We found CCNPs co-localized with mitochondria, lysosomes and endoplasmic reticulum as well as being abundant in the cytoplasm and the nucleus. Given the radical scavenging properties of cerium oxide and the widespread cellular disposition we observed, CNPs likely act as cellular antioxidants in multiple compartments of the cell imparting protection against a variety of oxidant injuries.