The now outdated perception of microorganisms of the gastrointestinal tract as pathogens or at best commensals continues to undergo remodeling. It is now clear that the microbiome of the gut participates in many activities including: digestion, ecologic protection from pathogens, and an increasingly appreciated immunoregulatory role in vertebrates. Studies of the complex interactions of microbes and hosts point to a convergence of two well-supported (though imperfect) hypotheses: the ‘hygiene hypothesis’ and the ‘fetal programming hypothesis’ proposed by Strachan and Barker, respectively. Our current understanding is one in which factors that exist before conception, during gestation, or occur perinatally in the infant milieu, in addition to exposures to nutrients and microbes, have the potential for long-term effects in the development of healthy offsprings and adults. Epidemiology, basic science and clinical research in such previously diverse areas of study such as microbiology, allergy, gastroenterology, endocrinology, immunology, rheumatology, infectious disease, perinatology, and nutrition are providing evidence that appropriate development and tendency towards the development of certain diseases are directly affected by intestinal microbe–host interactions. It appears likely that perinatal colonization of the gastrointestinal tract is a particularly pivotal process in which microbe-host programming occurs. Intestinal microbes and hosts have co-evolved that, when in appropriate balance, they produce and propagate a life-long mutualism.