Colonization with toxigenic Clostridium difficile may be associated with a wide spectrum of clinical presentation ranging from asymptomatic carriage to mild diarrhea to life-threatening colitis. Over the last 15 years, there has been a marked increase in the incidence of C. difficile infection, which predominantly affects elderly patients on antibiotics. More recently, there has been significant interest in the association between inflammatory bowel disease (IBD) and C. difficile infection. This review article discusses in some detail current knowledge of the mechanisms by which C. difficile toxins may mediate mucosal inflammation, together with the role of cell wall components of the microorganism in disease pathogenesis. Innate and adaptive host responses to C. difficile toxins and other components are described and include consideration of the potential role of known mucosal changes in IBD that may lead to an enhanced inflammatory response in the presence of C. difficile infection. Recent studies, which have characterized resident microbiota that may mediate protection against colonization by C. difficile, including their mechanisms of action, are also discussed. This includes the role of bile acids and 7α-dehydroxylase-expressing bacteria, such as Clostridium scindens. Recent studies suggest a higher carriage rate of C. difficile in patients with IBD. It is anticipated that future studies will determine the role of dysbiosis in IBD in predisposing to colonization with C. difficile.