The incidence and prevalence of Crohn's disease (CD) among children in developed countries is increasing. Although extensive progress has been made in the elucidation of the pathogenesis of the disease, its mechanism remains unknown. CD is likely to be the result of a complex interplay of both genetic and environmental factors (G × E). However, the specific elements underlying these interactions have not been defined. We propose that the underlying pathology of CD may be related to interactions between infections acquired either during intrauterine life and/or early childhood and DNA variants in the cytokine and the NOD2 genes. DNA variants in the latter could confer susceptibility by altering immune development and response to infectious agents. We present a molecular and epidemiological perspective on possible mechanisms underlying G × E. Investigating these and other pathways will be paramount for the appropriate identification of susceptible populations, so that preventive and/or therapeutic interventions could be adequately targeted.