The aim of this study is to identify current knowledge gaps in fate, exposure, and toxicity of engineered nanomaterials (ENMs), highlight research gaps, and suggest future research directions. Humans and other living organisms are exposed to ENMs during production or use of products containing them. To assess the hazards of ENMs, it is important to assess their physiochemical properties and try to relate them to any observed hazard. However, the full determination of these relationships is currently limited by the lack of empirical data. Moreover, most toxicity studies do not use realistic environmental exposure conditions for determining dose-response parameters, affecting the accurate estimation of health risks associated with the exposure to ENMs. Regulatory aspects of nanotechnology are still developing and are currently the subject of much debate. Synthesis of available studies suggests a number of open questions. These include (i) developing a combination of different analytical methods for determining ENM concentration, size, shape, surface properties, and morphology in different environmental media, (ii) conducting toxicity studies using environmentally relevant exposure conditions and obtaining data relevant to developing quantitative nanostructure-toxicity relationships (QNTR), and (iii) developing guidelines for regulating exposure of ENMs in the environment.