Asthma and atopy, classically associated with hyper-activation of the T helper 2 (Th2) arm of adaptive immunity, are among the most common chronic illnesses in developing nations worldwide. Emerging evidence has associated microbiota composition in residential house dust in very early-life with atopy and asthma development in childhood, suggesting that local environmental microbial exposures during the critical period of gut microbiome assembly in infancy, may influence this assemblage in a manner that dictates disease susceptibility. Murine studies have reinforced this hypothesis, indicating that exposure of mice to distinct house dust microbiota differentially modulates mucosal immune responses to airway allergen challenge. Independently, dietary interventions or oral supplementation of mice with a Lactobacillus species, promote immune tolerance to allergic sensitization at airway mucosal surfaces, via circulating gut microbiome-derived metabolites, further implicating the composition and activities of the gut microbiome in defining susceptibility to airway allergic sensitization. Finally, very recent human studies have indicated that gut microbiome perturbation, involving a loss of key immunomodulatory bacterial species, and associated metabolic dysfunction in very early infancy is associated with subsequent development of allergic asthma in childhood. Thus these data strongly point towards the need for early interventions involving gut microbiome manipulation in early life as a novel strategy for prevention of allergic airway disease in childhood.