The global prevalence of childhood asthma has undergone profound shifts, marked by a late-20th-century plateau in Western nations and a rapidly emerging epidemic across many developing countries. Traditional risk factors, such as air pollution, allergen exposure, and viral infections-fail to fully explain these trends. Instead, many birth cohorts and migrant studies strongly implicate changing early-life environments. Grounded in the hygiene and biodiversity hypotheses, this review explores the critical environmental determinants of childhood asthma. We synthesize global epidemiological data highlighting stark urban-rural disparities, drawing on seminal studies of European farming cohorts, US Amish and Hutterite communities, and cross-border Chinese populations. These populations collectively demonstrate the protective effects of early-life microbial exposure. We detail the current understanding of how environmental microbes and their metabolites dictate the maturation of the infant immune system, fostering systemic tolerance and preventing allergic trajectories. Furthermore, we evaluate emerging prospective primary intervention trials, including the ORBEX, TIGER, and MARTHA studies, which leverage microbial strategies in an attempt to alter the natural history of asthma development. Ultimately, the loss of environmental microbial diversity could be a primary driver of the allergy epidemic. Elucidating the underlying biological mechanisms of immune-microbe crosstalk and advancing prospective intervention trials will be essential for developing effective primary prevention strategies against childhood asthma.