Over the last decades, the use of engineered nanomaterials (ENMs) as delivery systems has been rising, finding applications in different fields, such as pharmaceutical, medical, and food technology. ENMs offer opportunities for targeted delivery, improved stability through the digestive conditions, increased solubility and bioavailability, and sustained release. Therefore, the risk assessment of those materials is essential to ensure their safety, in which in vitro models of the human gastrointestinal tract arise as fundamental tools to address this need. This chapter highlights the physiological features that play a significant role in a reliable risk assessment of orally administered ENMs and reviews the current advances and developments in in vitro models, pinpointing the opportunities that arise with organ-on-chip technology, organoids and the combination thereof. Moreover, we unveil the lag in using organ-on-a-chip systems to assess the fate and biological interactions of ENMs intended for oral administration despite the significant advances in the field. Finally, we outline that a closer collaboration between bioengineers and clinical toxicologists is fundamental to maximize the availability of human clinical data for in vitro model validation, fostering the wide acceptance of microfluidic models in pre-clinical studies.