Biomedical research aiming to understand the molecular basis of human lung tissue development, homeostasis and disease, or to develop new therapies for human respiratory diseases, requires models that faithfully recapitulate the human condition. This has stimulated biologists and engineers to develop in vitro organotypic models mimicking human respiratory tissues. In this chapter, we provide examples of different types of model systems ranging from simple unicellular cultures to more complex multicellular systems. The models contain, in varying degree, cell types present in real tissue in combination with different extracellular matrix components that can critically affect cell phenotype and function. We also describe how organotypic respiratory models can be combined with human innate immune cells, to better recapitulate tissue inflammation, a key component in, for example, infectious diseases. These models have the potential to provide new insights into lung physiology, tissue infection and inflammation, disease mechanisms, as well as provide a platform for identification of novel targets and screening of candidate drugs in human lung disorders.