The normal indigenous flora of the human gastrointestinal tract comprises a remarkably complex yet stable colony of more than 400 separate species, living in a symbiotic relationship with the human host. Stability of that flora is accomplished by multiple mechanisms including gastric acidity, gut motility, bile, products of immune cells in the gut epithelium, and competition between microorganisms for nutrients and intestinal binding sites. The indigenous flora influences multiple aspects of physiologic homeostasis and forms a key component of normal host defenses against infection by exogenous pathogens. Critical illness is associated with striking changes in patterns of microbial colonization, best described in the oropharynx and upper gastrointestinal tract. Pathological colonization occurs with the same species that is predominate in nosocomial infections, and descriptive studies suggest that such colonization is a risk factor for infection. Moreover, prophylactic measures that prevent pathological gut colonization in experimental circumstances reduce rates of nosocomial infection in critically ill patients and, in the case of selective decontamination of the digestive tract, reduce mortality risk. Conventional approaches to infectious diseases have conceptualized microorganisms as inimical and focused on eradicating them as rapidly and fully as possible. Insights from the study of critically ill patients suggest that that relationship is better understood as a symbiotic one and that preservation, rather than elimination, of the indigenous flora provides the greatest promise of clinical benefit to this vulnerable population.