Over the past two decades, it has become clear that against earlier assumptions, the respiratory tract is regularly populated by a variety of microbiota even down to the lowest parts of the lungs. New methods and technologies revealed distinct microbiome compositions and developmental trajectories in the differing parts of the respiratory tract of neonates and infants. In this review, we describe the current understanding of respiratory microbiota development in human neonates and highlight multiple factors that have been identified to impact human respiratory microbiome development including gestational age, mode of delivery, diet, antibiotic treatment, and early infections. Moreover, we discuss to date revealed respiratory microbiome-disease associations in infants and children that may indicate a potentially imprinting cross talk between microbial communities and the host immune system in the respiratory tract. It becomes obvious how insufficient our knowledge still is regarding the exact mechanisms underlying such cross talk in humans. Lastly, we highlight strong findings that emphasize the important role of the gut-lung axis in educating and driving pulmonary immunity. Further research is needed to better understand the host - respiratory microbiome interaction in order to enable the translation into microbiome-based strategies to protect and improve human respiratory health from early childhood.