Asthma has a high prevalence worldwide, and contributes significantly to the socioeconomic burden. According to a classical paradigm, asthma symptoms are attributable to an allergic, Th2-driven airway inflammation that causes airway hyperresponsiveness and results in reversible airway obstruction. Diagnosis and therapy are based mainly on these pathophysiologic concepts. However, these have increasingly been challenged by findings of recent studies, and the frequently observed failure in controlling asthma symptoms. Important recent findings are the protective "farm effect" in children, the possible prenatal mechanisms of this protection, the recognition of many different asthma phenotypes in children and adults, and the partly disappointing clinical effects of new targeted therapeutic approaches. Systems biology approaches may lead to a more comprehensive view of asthma pathophysiology and a higher success rate of new therapies. Systems biology integrates clinical and experimental data by means of bioinformatics and mathematical modeling. In general, the "-omics" approach, and the "mathematical modeling" approach can be described. Recently, several consortia have been attempting to bring together clinical and molecular data from large asthma cohorts, using novel experimental setups, biostatistics, bioinformatics, and mathematical modeling. This "systems medicine" approach to asthma will help address the different asthma phenotypes with adequate therapy and possibly preventive strategies.