Engineered nanomaterials are a product of nanotechnology, and have an intentionally produced structure at the scale of approximately 1–100 nm. These materials demonstrate properties that depend on a carefully controlled and implemented nanostructure; the close dependency between this structure and material functionality challenges how quantitative risk assessment is applied to some engineered nanomaterials. For instance, nanostructure-related functionality may lead to health risks that depend on properties such as particle size, surface area, and shape. There is evidence that the size, surface area, surface chemistry, and possibly shape of some engineered nanomaterials may determine transport and response within the body. Quantitative risk assessment of these materials will depend on determining when they behave differently from conventional materials, what properties are associated with their potential impact, and how exposure, dose and response can be most appropriately evaluated. At present, insufficient data and incomplete methodologies are available for conducting comprehensive quantitative risk assessments on many emerging nanomaterials. Until more comprehensive information is available, it will be necessary to identify those nanomaterials that present unique challenges, and to use existing information together with expert extrapolation as a basis for qualitative and semi-quantitative risk assessment.