The most commonly used antibiotics in Crohn's disease are nitroimidazoles and macrolides often combined with corticosteroids or sulfasalazine. There has been interest in a mycobacterial involvement in Crohn's disease since its earliest description. It is not recognized that Mycobacterium avium subspecies paratuberculosis, a proven but uncommon cause of human disease, is widespread in the human food chain especially in dairy products and beef. M. paratuberculosis has been identified in tissues from a higher proportion of Crohn's disease patients than controls, suggesting that it may be one of the causes of Crohn's disease. We review the large number of antibiotic trials in Crohn's disease. Although studies have been performed with many different protocols and variations in the definition of success, preliminary reports of multiple drug therapies are encouraging. Nevertheless, large-well designed preferably placebo-controlled studies are needed before one could recommend such therapy.