Defensins are antimicrobial peptides produced by professional phagocytes, Paneth cells, and intestinal epithelial cells. In addition to their potent antimicrobial activity, defensins can also modulate the function and movement of neutrophils, monocytes, T-lymphocytes, dendritic cells, and epithelial cells. Paneth cells are equipped with multiple defensins and antimicrobial proteins and usually reside in the small intestine. This review highlights the diverse functions of defensins and changes in defensin expression and Paneth cell proliferation in Crohn's disease, ulcerative colitis, and animal models of inflammatory bowel disease. Current data favor the hypothesis that defensins and Paneth cells may play important roles in the maintenance of intestinal immune homeostasis through 2 distinct mechanisms. The first mechanism is to act as effector molecules and cells against pathogenic microbes, while the second is to regulate host immune cell functions.