This chapter discusses the fundamental background of interspecies models along with interspecies quantitative structure–toxicity relationship models, their basic differences, and their advantages in nanotoxicity prediction in the present time. It aims to understand the basic principles and required components for developing a successful interspecies model for nanotoxicity. Several groups of authors have presented appropriate insight into the mechanism of action (MOAs) of a diverse range of chemicals through the development of interspecies correlation models. The selection of a species for a specific endpoint is the most important criterion of interspecies modeling. There lies the importance of interspecies/i-quantitative structure–toxicity relationship (QSTR) model construction as the MOA-specific interspecies models may assist in the prediction of species sensitivity by dropping improbability in species extrapolation. The QSTR is competent for evaluating structural features and physicochemical properties responsible for toxicity of nanomaterial (NMs). Due to toxicity testing and risk assessment of diverse NMs, there is an increase in animal testing.