Crohn's disease is often considered an autoimmune condition, based on the observations of a histopathological inflammatory process in the absence of identifiable causal microorganism(s) and that immune-modulating therapeutics result in diminished host-directed inflammatory pathology. However, the evidence for a self-targeted immune response is unproven; thus, the instigating and perpetuating forces that drive this chronic inflammation remain unknown. In recent years, a convergence of findings from different fields of investigation has led to a new paradigm, where Crohn's disease appears to be the consequence of an intrinsic innate immune deficiency. While genomic/postgenomic studies and functional immunologic investigations offer a common perspective, critical details of the processes involved require further elaboration. In this review, we place this new model in the context of the emerging literature on non-HIV immune deficiencies, to compare and contrast what is known about proven intrinsic (primary) immune deficiencies to the nascent understanding of Crohn's disease. We then re-evaluate postgenomic research, looking at the functional importance of Crohn's disease-associated mutations and polymorphisms, to delineate points of consensus and issues requiring further study. We ask whether the immunologic profile can guide predictions as to which microbial triggers could exploit these defects and thereby initiate and/or perpetuate chronic enteritis. Finally, we outline potential clinical implications of this model, from immunologic assessment of patients to the selection of therapeutic interventions.