Crohn's disease (CD) is often considered to be an autoimmune condition or, alternatively, an autoinflammatory condition, based on the observation of host-directed inflammatory processes. However, the underlying basis of this deleterious inflammatory response remains elusive. Recent findings from genetic and genomic studies have altered the perspective on the pathogenesis of CD, hinting at defects in innate immune sensing of intracellular bacteria and the handling of these organisms through autophagy. These findings are consistent with emerging data from immunological studies that point to a systemic immune deficiency in CD patients. Both sets of data (genetic predisposition and immunodeficiency) are consistent with the longstanding hypothesis that mycobacteria might be involved in the etiology of CD. In this article, we discuss the convergence of these three lines of investigation and highlight important knowledge gaps required in order to address the mycobacterial hypothesis with greater clarity. In the coming years, clinical immunological investigations should focus on defining the specificity of functional immune defects with regards to microbes and their associated ligands. Should CD result from a dysfunctional host-pathogen interaction, elucidation of the microbes that can exploit such defects to induce a chronic inflammatory disease is critical for the development of subsequent diagnostic assays and clinical interventions.