Asthma and chronic obstructive pulmonary disease (COPD) show similarities and substantial differences. The Dutch hypothesis stipulated that asthma and COPD have common genetic and environmental risk factors (allergens, infections, smoking), which ultimately lead to clinical disease depending on the timing and type of environmental exposures (Postma and Boezen, Chest 2004;126:96S-104S). Thus, a particular group of shared genetic factors may lead to asthma when combined with specific environmental factors that are met at a certain stage in life, whereas combination with other environmental factors, or similar environmental factors at a different stage in life, will lead toward COPD. Multiple genes have been found for asthma and COPD. In addition to genes unique to these diseases, some shared genetic risk factors exist. Moreover, there are both common host risk factors and environmental risk factors for asthma and COPD. Here we put forward, based on the data available, that genes that affect lung development in utero and lung growth in early childhood in interaction with environmental detrimental stimuli, such as smoking and air pollution, are contributing to asthma in childhood and the ultimate development of COPD. Additional genes and environmental factors then drive specific immunological mechanisms underlying asthma, and others may contribute to the ultimate development of specific subtypes of COPD (i.e., airway disease with mucous hypersecretion, small airway disease, and emphysema). The genetic predisposition to the derailment of certain pathways may further help to define subgroups of asthma and COPD. In the end this may lead to stratification of patients by their genetic make-up and open new therapeutic prospects.