It is well established that smoking cigarettes is associated with Crohn's disease (CD) and that non-smoking is associated with ulcerative colitis (UC). Furthermore, there is convincing evidence that smoking cigarettes has a negative effect on the course of CD, and that smoking cigarettes may improve the disease severity or have a 'protective' effect in some patients with UC. Despite these well-described associations, the mechanism by which cigarette smoking affects CD and UC is not known. Researchers have studied the systemic effects, cellular and humoral immune effects, mucosal changes, and the intestinal permeability changes with inflammatory bowel disease (IBD) and smoking. To date, none of these studies adequately explains the observed clinical patterns. It has been assumed that nicotine is the active agent in these associations, but clinical trials of nicotine chewing gum and transdermal nicotine in UC have shown limited benefit, and have been complicated by significant side-effects. Topical delivery systems for nicotine therapy are currently under development and await future clinical trials.