Epithelial cells contribute to innate immunity by releasing antimicrobial peptides (AMPs) onto mucosal surfaces. In the small bowel, Paneth cells at the base of the crypts of Lieberkühn secrete alpha-defensins and additional AMPs at high levels in response to cholinergic stimulation and when exposed to bacterial antigens. The release of Paneth cell products into the crypt lumen is inferred to protect mitotically active crypt cells that renew the epithelial cell monolayer from colonization by potentially pathogenic microbes and to confer protection from enteric infection. The most compelling evidence for a Paneth cell role in enteric resistance to infection is evident from studies of mice transgenic for a human Paneth cell alpha-defensin, HD-5, which are completely immune to infection and systemic disease from orally administered Salmonella typhimurium. Alpha-defensins in Paneth cell secretions may also interact with bacteria in the intestinal lumen above the crypt-villus boundary and influence the composition of the enteric microbial flora, but that remains to be demonstrated.