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This report is based on a review of the various investigations attempting to determine the etiology of Crohn's disease. It has paid special attention to three main possible etiologic mechanisms reported in the literature up to the time of this review; namely, immunologic, unknown transmissible agents or known such as L-forms, protoplasts, or spheroplasts, viral or infectious RNA and/or DNA, and a combination of the preceding causative possibilities. It has discussed the unrewarding immunological mechanisms, the failure to confirm the various investigations suggesting a transmissible agent and/or the speculations concerning the possible combination of factors. It also has included the remarks of Sacchar and Auslander, who stated that four important pieces were missing to allow acceptance of transmissible agent as the cause of Crohn's disease. This review has demonstrated that up to the present time the etiology of Crohn's disease has remained a puzzle and concluded that further investigations are necessary to resolve the etiology of Crohn's disease with the suggestion that evidence for an infectious agent will require experiments that satisfy Koch's postulates.