The normal upper and lower respiratory tract are not colonized by enteric gram-negative bacteria (EGNB), but when serious illness develops, both sites may harbor these organisms. Colonization at either site is more likely when the severity of illness increases, and in critically ill patients, Pseudomonas species are the most common colonizing organisms, especially in the tracheobronchial tree. Many of the risk factors for colonization by EGNB have also been recognized as predisposing conditions for nosocomial pneumonia, and colonization may precede and predict this infection. Colonization should be viewed as a marker of a sick patient who had multiple host impairments; it is these defects that often allow colonization to progress to invasive infection. One pathogenetic mechanism that mediates colonization is an increase in epithelial cell bacterial adherence for EGNB. Many of the clinical conditions that favor colonization lead to an alteration in epithelial cell surface susceptibility to bacterial binding. Factors that influence adherence include cellular variables, bacterial surface characteristics and exoproducts, and the microenvironmental conditions at the airway surface. In order for adherence to mediate colonization, mucociliary clearance and other lower respiratory tract defenses must be abnormal. Based on an understanding of colonization pathogenesis, rational strategies for nosocomial pneumonia prophylaxis may emerge.