In this chapter, we provide an overview of recent advancements related to the safety assessment of engineered nanomaterials (ENMs) using alternatives to animal testing strategies. Advanced risk assessment computational procedures include new methods for characterizing and describing the complex structures of ENMs, development of computational models predicting adverse effects, extension of “read-across” approaches taking into account different aspects of ENM similarity, integration of various testing strategies using a “weight-of-evidence” approach, and using omics data and pathways analysis technologies to provide insights into ENM mechanisms that potentially could induce toxicity.