Advanced cell culture systems, such as airway organoids and co-cultures of epithelial cells with immune cells, could serve as a powerful platform to study viral infection and pathogenesis. Towards this goal, we describe the development of two new human lung culture systems and their use in host-pathogen interactions studies and in drug screening applications. First, co-cultures of human bronchial epithelial cells (hBECs) and blood-derived macrophages were established in a complex air-liquid interface model. This system was used to determine the role of different macrophage phenotypes (M0, M1, and M2) following respiratory syncytial virus infection. Macrophage subtypes were shown to be influenced by their microenvironment, with M1-like macrophages considerably decreasing the initial infection, whereas M0- and M2-like helped potentiate it. Secondly, hBECs were used to generate apical out airway organoids (Ap-O AO) in an ECM-free, serum-free and easily scalable workflow. This novel 3D organoid culture model exposes the apical side of the epithelium to the environment. Infection of Ap-O AO with influenza A, influenza B, rhinovirus-A16, or enterovirus-D68 produced high viral RNA titers (approximately 5.5 log10 copies per sample) and strong cytopathogenic effects, whereas administration of two antivirals, rupintrivir and itraconazole, significantly rescued the infection effects. In summary, we describe the generation and use of two new models to study infectious disease pathogenesis in vitro and assess antiviral drug effects.