The respiratory system is the main site of gas exchange with the external environment in complex terrestrial animals. Within the trachea and lungs are multiple different tissue niches each consisting of a myriad of cells types with critical roles in air conduction, gas exchange, providing important niche specific cell-cell interactions, connection to the cardiovascular system, and immune surveillance. How the respiratory system responds to external insults and executes the appropriate regenerative response remains challenging to study given the plethora of cell and tissue interactions for this to occur properly. This review will examine the various cell types and tissue niches found within the respiratory system and provide a comparison between mouse and human lungs and trachea to highlight important similarities and differences. Defining the critical gaps in knowledge in human lung and tracheal regeneration is critical for future development of therapies directed towards respiratory diseases.