An increased understanding of nanoparticle toxicity and its impact on human health is essential to enable a safe use of nanoparticles in our society. The aim of this study is to investigate the role of a Trojan horse type mechanism for the toxicity of Ag-nano and CuO-nano particles and their corresponding metal ionic species (using CuCl2 and AgNO3), i.e., the importance of the solid particle to mediate cellular uptake and subsequent release of toxic species inside the cell. The human lung cell lines A549 and BEAS-2B are used and cell death/membrane integrity and DNA damage are investigated by means of trypan blue staining and the comet assay, respectively. Chemical analysis of the cellular dose of copper and silver is performed using atomic absorption spectroscopy. Furthermore, transmission electron microscopy, laser scanning confocal microscopy, and confocal Raman microscopy are employed to study cellular uptake and particle-cell interactions. The results confirm a high uptake of CuO-nano and Ag-nano compared to no, or low, uptake of the soluble salts. CuO-nano induces both cell death and DNA damage whereas CuCl2 induces no toxicity. The opposite is observed for silver, where Ag-nano does not cause any toxicity, whereas AgNO3 induces a high level of cell death. In conclusion: CuO-nano toxicity is predominantly mediated by intracellular uptake and subsequent release of copper ions, whereas no toxicity is observed for Ag-nano due to low release of silver ions within short time periods.