Abstract The application of human-induced pluripotent stem cells (iPSCs) in modeling infection is an important tool in the study of infection biology and disease pathogenesis. Improved methodologies have allowed for the generation of reproducible and stable pluripotent stem cell lines from a range of adult somatic origins and underlying genetics. Differentiation protocols have been developed for the generation of diverse cell types found among complex tissue organs. Here, we summarize the development and the challenges of iPSC development, the subsequent diversity of derived cellular populations such as macrophages, cardiomyocytes, neural cells, and hepatocytes and their application to infection modeling and immunology. As physiologically relevant cells from human organ tissues, human iPSCs provide a powerful method to study species-specific intracellular infections from bacterial, viral, and parasitic sources, as well as genetic influences. Major challenges are still evident and to fully recapitulate host organ systems, 3D structures (i.e., organoids) have been developed showing mature morphology to further model the organs of interest.