The use of human cell lines and primary cells as in vitro models represents a valuable approach to study cellular responses to infection. However, with the advent of new molecular technologies and tools available, there is a growing need to develop more physiologically relevant systems to overcome cell line model limitations and better mimic human disease. Since the discovery of human stem cells, its use has revolutionised the development of in vitro models. This is because after differentiation, these cells have the potential to reflect in vivo cell phenotypes and allow for probing questions in numerous fields of the biological sciences. Moreover, the possibility to combine the advantages of stem cell-derived cell types with genome editing technologies and engineered 3D microenvironments, provides enormous potential for producing in vitro systems to investigate cellular responses to infection that are both relevant and predictive. Here, we discuss recent advances in the use of human stem cells to model host-pathogen interactions, highlighting emerging technologies in the field of stem cell biology that can be exploited to investigate the fundamental biology of infection. TAKE AWAYS: hPSC overcome current limitations to study host-pathogen interactions in vitro. Genome editing can be used in hPSC to study cellular responses to infection. hPSC, 3D models and genome editing can recreate physiological in vitro systems.