Crohn's disease, an inflammatory bowel disease of unknown cause, was initially considered to have an infectious etiology. As the infectious agent could not be identified, it was grouped among the immune disorders. As a result, research and clinical trials were directed towards the autoimmune theory and patients were treated with steroids, immunomodulators, aminosalicylates and, most recently, anti-tumor necrosis factor-alpha. Because of the inconsistency of treatment success and the failure to cure Crohn's disease, many physicians turned to antibiotics in search for alternative solutions, especially when other regimens failed. Attention has recently been directed toward possible infectious causes of Crohn's disease. Although it is still unknown whether microbial agents are etiologically involved in the pathogenesis of Crohn's disease, there has been a growing interest in trying antibiotics in the management of Crohn's disease. This review summarizes the data available regarding antibiotic treatment of Crohn's disease in relation to a possible mycobacterial etiology. Multidrug therapies are in clinical trials and the results of these randomized, controlled, double-blind studies are needed before guidelines about whether to include antibiotics as part of the treatment of Crohn's disease management can be made.