Crohn's disease is a chronic inflammatory disorder primarily affecting the gastrointestinal tract. Its clinical manifestations arise from a substantial infiltration of the intestinal mucosa by activated leukocytes and the downstream consequences of chronic inflammation. The underlying cause driving this immunological reaction remains poorly understood. A number of hypotheses have been proposed, most of which postulate a primary over-activation of the immune response, based on the pathological appearances of active Crohn's lesions. Interestingly, none of these theories have been mechanistically proven. It is possible that the immunological events responsible for disease initiation are quite different from those contributing to its persistence and propagation. A substantial body of data has emerged in recent years to suggest that the primary defect in Crohn's disease is actually one of relative immunodeficiency. This review considers the evidence for such a phenomenon in contrast to alternative prevailing hypotheses and attempts to address some of the potential paradoxes that it generates.