AbstractNanoparticles (NPs) can potentially cause adverse effects on organ, tissue, cellular, subcellular, and protein levels due to their unusual physicochemical properties (e.g., small size, high surface area to volume ratio, chemical composition, crystallinity, electronic properties, surface structure reactivity and functional groups, inorganic or organic coatings, solubility, shape, and aggregation behavior). Metal NPs, in particular, have received increasing interest due to their widespread medical, consumer, industrial, and military applications. However, as particle size decreases, some metal‐based NPs are showing increased toxicity, even if the same material is relatively inert in its bulk form (e.g., Ag, Au, and Cu). NPs also interact with proteins and enzymes within mammalian cells and they can interfere with the antioxidant defense mechanism leading to reactive oxygen species generation, the initiation of an inflammatory response and perturbation and destruction of the mitochondria causing apoptosis or necrosis. As a result, there are many challenges to overcome before we can determine if the benefits outweigh the risks associated with NPs. WIREs Nanomed Nanobiotechnol 2010 2 544–568This article is categorized under: Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials