This article discusses critical issues and opportunities going forward in nanotechnology environmental, health, and safety (nanoEHS) research from the perspective of Federal Government Agency participants in the United States (U.S.) National Nanotechnology Initiative (NNI) interagency Nanotechnology Environmental and Health Implications Working Group (NEHI). NEHI is responsible for coordination of Federal Science Agency nanoEHS research. As participants in NEHI, we examine these critical issues from an integrated, transdisciplinary perspective, noting examples of impactful research efforts that are advancing knowledge in these areas. Major themes identified include detection, measurement, and characterization of real-world nanomaterial exposures, understanding the biological transformation of nanomaterials and their potential (eco) toxicological implications, understanding the landscape of nanotechnology-enabled products in commerce, and advancing the EHS knowledge infrastructure related to nanomaterials and nanotechnology. Significant investments in nanoEHS research over two decades have led to establishment of a unique and diverse multidisciplinary, multisector community of practice. These investments must be leveraged and adapted not only to future nanotechnology, but also to use as a model for accelerating acquisition of safe and reliable risk information for tomorrow's emerging technologies for a more sustainable and competitive world.