It is often assumed that nanotechnology (NT) holds the potential to provide a substantial contribution to the solution of various ecological problems, including high consumption of energy and materials and the generation of waste. However, problems surrounding the use and release of hazardous substances remain largely unexplored. For this reason, the Scientific Technical Option Assessment (STOA) Panel of the European Parliament initiated a study on “The Role of Nanotechnology in Chemical Substitution.” The subject and aim of the study was an investigation into preexisting and potential applications of NT that could lead to a reduction in hazardous substances by providing substitutes for them. In terms of method, it was based on electronic searches of the literature, expert interviews, and an expert workshop. This article discusses the results of the project. It focuses on the methodological challenges and the principal problems resulting from a combination of the broad and ill-defined concept of NT and the specific concept of hazardous substances. The hazardous substances addressed had to be reduced to a manageable number, and the term substitution was understood according to the characteristics of NT and the way in which the latter could reduce the use of hazardous substances. Although several applications of NT were identified that could lead to a considerable reduction in the use of hazardous substances, ambiguities in both the concept of NT and the concept of substitution in relation to NT prevent a comprehensive assessment of the potential of NT in respect to substitution.