With the changing epidemiology of Crohn's disease (CD) and intestinal tuberculosis (ITB), we are in an era where the difficulty facing physicians in discriminating between the two diseases has increased, and the morbidity and mortality resulting from a delayed diagnosis or misdiagnosis is considerably high. In this article, we examine the changing trends in the epidemiology of CD and ITB, in addition to clinical features that aid in the differentiation of both diseases. The value of various laboratory, serological, and the tuberculin skin tests are reviewed as well. The use of an interferon-gamma-release assay, QuantiFERON-TB Gold, in the workup of these patients and its value in populations where the bacillus Calmette-Guérin vaccine is still administered is discussed. Different radiological, endoscopic, and pathological similarities and features that can aid the clinician in reaching a rapid diagnosis are reviewed as well. The association between mycobacteria and CD, the concerns with the practice of antituberculosis medication trials in areas where tuberculosis (TB) is endemic, as well as extrapulmonary TB induced by the use of antitumor necrosis factor-alpha agents are delineated in this article. Furthermore, we propose an algorithm for the investigation of patients in whom the differential diagnosis encompasses CD and ITB.