Clues from patient and experimental animal studies suggest that events occurring early in the pathogenesis of Crohn's disease are related to an inability of the immune system to eradicate one or a number of luminal antigens resulting in persistent T cell and macrophage activation. Whether the primary abnormality rests with the nature of the luminal antigen, disturbances of antigen uptake by the mucosa, antigen handling by macrophages, or macrophage-T cell interactions remains unresolved. Given the heterogeneity of clinical presentations and experimental data, Crohn's disease may be a group of disorders associated with a number of primary defects.