Over the past two decades there has been a dramatic increase worldwide in both incidence and severity of Clostridium difficile infection (CDI). Paralleling the rising incidence of CDI in the general population, there has been an even higher increase in the incidence of CDI among patients with inflammatory bowel disease (IBD). CDI may mimic a flare of IBD as symptoms and laboratory parameters are often similar, and therefore, screening for CDI is recommended at every flare in such patients. Enzyme immunoassay to detect Clostridium difficile toxin A and B in stool is still the most widely used test for CDI diagnosis despite its low sensitivity. Metronidazole for mild/moderate CDI,and vancomycin for severe CDI are the preferred agents for the treatment of infection. CDI has a negative impact both on short- and long- term IBD outcomes, increasing the need for surgery, as well as the mortality rate and healthcare costs. All gastroenterologists and surgeons should have a high index of suspicion for CDI when evaluating a patient with IBD flare, as prompt diagnosis and adequate treatment of infection improve outcomes. Measures must be taken to prevent spreading of infection in gastroenterology /surgery settings.