Birth cohort studies have produced significant advances toward understanding how genetic and environmental factors contribute to the inception of asthma and related allergic diseases. Histopathologic, physiologic, microbiologic, and immunologic findings indicate that critical developmental windows exist in which these various factors either alone or in concert induce the expression of the childhood asthma phenotype. The microbiome in early life clearly influences immune development and asthma. Early environmental exposures, including those related to the home, parents, siblings, pets, and pests, are all likely to influence patterns of microbial colonization and also might shape immune responses to allergens and viruses. As with other contributing factors, there appear to be windows of opportunity in early life when microbial exposures have the greatest effect on these processes. Recent studies of bacterial metabolic products and their effects might suggest new strategies for immune modulation in early life.