The prevalence of allergy and asthma has increased significantly over the past several decades, particularly so in industrialized nations where environmental exposures and lifestyles have rapidly diverged from those with which humans evolved. Multifactorial and heterogenous, there is an urgent need to understand the origins of allergy and asthma and develop effective interventions for precision treatment and prevention. Epidemiological studies have identified prenatal and early-life exposures that prevent or promote disease in childhood, a number of which exert strong selective pressures on the types, functions, epigenetic modifications, and development of cellular populations (microbial and immune) critical to immune training, function, and asthma pathogenesis. Technological advances in the fields of human genetics, epigenetics, immunology, and microbiome research have more recently expanded our view of human biology. Studies employing these tools individually have uncovered key relationships with allergy and asthma development across temporal and geospatial gradients. These observations suggest that although these factors are important in determining asthma risk, their influence is likely integrative, contextual, and cumulative across temporal gradients. Clearly, a range of extrinsic and intrinsic factors collude to promote disease development. Central to the integration and phenotypic translation of these exposures are cellular populations, in particular, maternal prenatal, and early-life postnatal microbial and immune cells, whose activities and interactions set in motion successional programming events that govern developmental trajectories and downstream health outcomes. This Perspective discusses the most salient of these events and proposes an actionable research scenario that integrates and contextualizes them.