Colonization of the extremely preterm infant's gastrointestinal tract and skin begins in utero and is influenced by a variety of factors, the most important including gestational age and environmental exposures. The composition of the intestinal and skin microbiota influences the developing innate and adaptive immune responses with short-term and long-term consequences including altered risks for developing necrotizing enterocolitis, sepsis, and a wide variety of microbe-related diseases of children and adults. Alteration of the composition of the microbiota to decrease disease risk is particularly appealing for this ultra-high-risk cohort that is brand new from an evolutionary standpoint.