Chronic lung diseases including asthma are characterized by an abnormal immune response and active tissue remodeling. These changes in the architecture of the tissue are a fundamental part of the pathology across the life course of patients suffering from asthma. Current treatments aim at dampening the immune system hyperactivation, but effective drugs targeting stromal or acellular structures are still lacking. This is mainly due to the lack of a detailed understanding of the composition of the large airways and the cellular interactions taking place in this niche. We and others have revealed multiple aspects of the spatial architecture of the airway wall in response to airborne insults. In this review, we discuss four elements that we believe should be the focus of future asthma research across the life course, to increase understanding and improve therapies: (i) specialized lung niches, (ii) the 3D architecture of the epithelium, (iii) the extracellular matrix, and (iv) the vasculature. These components comprise the main stromal structures at the airway wall, each playing a key role in the development of asthma and directing the immune response. We summarize promising future directions that will enhance lung research, ultimately benefiting patients with asthma.