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The last decade of microbiome research has highlighted its fundamental role in systemic immune and metabolic homeostasis. The microbiome plays a prominent role during gestation and into early life, when maternal lifestyle factors shape immune development of the newborn. Breast milk further shapes gut colonization, supporting the development of tolerance to commensal bacteria and harmless antigens while preventing outgrowth of pathogens. Environmental microbial and lifestyle factors that disrupt this process can dysregulate immune homeostasis, predisposing infants to atopic disease and childhood asthma. In health, the low-biomass lung microbiome, together with inhaled environmental microbial constituents, establishes the immunological set point that is necessary to maintain pulmonary immune defense. However, in disease perturbations to immunological and physiological processes allow the upper respiratory tract to act as a reservoir of pathogenic bacteria, which can colonize the diseased lung and cause severe inflammation. Studying these host-microbe interactions in respiratory diseases holds great promise to stratify patients for suitable treatment regimens and biomarker discovery to predict disease progression. Preclinical studies show that commensal gut microbes are in a constant flux of cell division and death, releasing microbial constituents, metabolic by-products, and vesicles that shape the immune system and can protect against respiratory diseases. The next major advances may come from testing and utilizing these microbial factors for clinical benefit and exploiting the predictive power of the microbiome by employing multiomics analysis approaches. [ABSTRACT FROM AUTHOR]