Early life influences are crucial for the development of distinct childhood asthma phenotypes, which are currently included under the term asthma syndrome. Improved characterisation of different childhood asthma phenotypes will help to elucidate specific underlying immune mechanisms-namely, endotypes. Besides genetics, epigenetics and environmental factors have an effect on innate and adaptive immune regulatory networks. Crucial determining factors for complex immune regulation and barrier function include family history of atopy, respiratory infections, microbiome, and nutrition. Recent diagnostic approaches, including biomarkers, might offer a unique opportunity to improve definitions of asthma sub-phenotypes, prediction of outcome, and treatment options, by referring to the underlying pathophysiology. For prevention and patient-individualised medicine, a multifactorial approach incorporating deep phenotyping and mathematical models for analysis to extend our present knowledge is needed.