At birth, the newborn leaves the germ-free intrauterine environment and enters a highly contaminated extrauterine world, which requires potent host defenses to prevent disease. Intestinal defenses develop during gestation and have the capacity to respond but first must be exposed to colonizing bacteria. I review the importance of bacterial colonization for the appearance of normal mucosal immune function and the clinical consequences of inadequate colonization with regard to development of disease. For example, we now know that an imbalance in T-helper (Th) cells (e.g., Th2 levels greater than Th1 levels) can predispose to autoimmune disease and gut inflammation or disease, such as necrotizing enterocolitis. As we determine the role of bacterial colonization in the gut (bacterial-epithelial "cross talk"), we should have more-appropriate ways to modulate the gut immune responses-for example, by use of probiotics to prevent the expression of these gastrointestinal diseases.