Immune homeostasis at mucosal level results from controlled response to intestinal luminal antigens. Recent insights into the nature of inflammatory bowel diseases, derived mainly from studies of experimental models of colonic inflammation, strongly suggest that they can result from a loss of immune tolerance to antigens in the bacterial microflora. Investigations of the regulatory mechanisms operating at the mucosal level suggest that regulatory cells reactive to the intestinal microflora might play a role in cross-reactive protection toward different antigens. Expansion of microflora-reactive regulatory cells by probiotic administration is able to protect from experimental colitis. Characterization of regulatory cells in response to normal commensal flora, the basis of their development and the role of innate immunity in this process might contribute to the understanding of the development of inflammatory bowel diseases.