Nanoparticles are recently-introduced industrial products which impact on the environment and on human health is intensely debated, due in part to their long persistence in vivo. Most of the toxicological research carried to date on nanoparticles follows very classical tracks, so that little is known yet on their mechanisms of toxicity. Furthermore, classical toxicology on laboratory animals cannot mimick the high diversity of situations encountered in human populations, so that mechanistic data are needed to make predictions that could be applied in human toxicology of nanoparticles. Because of their major scavenging function and their role in inflammation, macrophages are one of the major cell types to study when working on nanoparticles. In order to gain new insights on the interaction of nanoparticles with macrophages, we carried out a proteomic screen on cells treated with different nanoparticles (e.g. copper oxide, zinc oxide, metallic silver or silica). Very different responses have been observed : Copper oxide induces mainly a mitochondrial response and a strong response at the glutathione level. Zinc oxide rather induces a proteasomal and a metabolic response (glucolysis and pentose phosphate pathways). Proteomics was followed by targeted studies aiming at validating the proteomic results and at investigating major functions of macrophages (e.g. phagocytosis and cytokine production). In this way, we could demonstrate a role of DNA repair pathways for zinc oxide and silica nanoparticles, as well as a critical role of glutathione and heme oxygenase for survival to a copper oxide challenge. Mitochondrial dysfunction is also prominent following exposure to zinc oxide or copper oxide, and much less important following exposure to silver or silica. Different changes in the actin cytoskeleton were also observed in response to the nanoparticles tested. In conclusion, this combined approach has provided new ideas on how nanoparticles can exert their toxic effect.