Engineered nanomaterials (ENMs) have tremendous potential to produce beneficial technological impact in numerous sectors in society. Safety assessment is, of course, of paramount importance. However, the myriad variations of ENM properties makes the identification of specific features driving toxicity challenging. At the same time, reducing animal tests by introducing alternative and/or predictive in vitro and in silico methods has become a priority. It is important to embrace these new advances in the safety assessment of ENMs. Indeed, remarkable progress has been made in recent years with respect to mechanism-based hazard assessment of ENMs, including systems biology approaches as well as high-throughput screening platforms, and new tools are also emerging in risk assessment and risk management for humans and the environment across the whole life-cycle of nano-enabled products. Here, we highlight some of the key advances in the hazard and risk assessment of ENMs.