While nanomaterial applications in the agrifood value chain are rapidly increasing, concerns related to their safety must be carefully considered. For marketing authorization, regulation requires specific or suitable methods to demonstrate safety of nanobased products. The safe-by-design approach extends this concept by considering safety implications as early as possible in the innovation process, to reduce risks and uncertainties while balancing benefits and costs. The European Food Safety Authority supports this approach by providing an operative definition of nanomaterial and dedicated guidelines for risk assessment. From this perspective, the chapter discusses the current approaches for safety evaluation of nanomaterials in food-related applications, ranging from the regulatory framework and its future evolution to the currently available methodological tools for nanomaterial physicochemical characterization and in vitro testing.