The Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) mother-child cohorts have provided a foundation of 25 years of research on the origins, prevention, and natural history of childhood asthma and related disorders. COPSAC’s approach is characterized by clinical translational research with longitudinal deep phenotyping and exposure assessments from pregnancy, in combination with multi-omic data layers and embedded randomized controlled trials. One trial showed that fish oil supplementation during pregnancy prevented childhood asthma and identified pregnant women with the highest benefits from supplementation, thereby creating the potential for personalized prevention. COPSAC revealed that airway colonization with pathogenic bacteria in early life is associated with an increased risk of asthma. Further, airway bacteria were shown to be a trigger of acute asthma-like symptoms, with benefit from antibiotic treatment. COPSAC identified an immature gut microbiome in early life as a risk factor for asthma and allergy and further demonstrated that asthma can be predicted by infant lung function. At a molecular level, COPSAC has identified novel susceptibility genes, early immune deviations, and metabolomic alterations associated with childhood asthma. Thus, the COPSAC research program has enhanced our understanding of the processes causing childhood asthma and has suggested means of personalized prevention and treatment.