The gastrointestinal tract seems to play a central role in the pathogenesis of pneumonia in critically ill patients. During the past decade, several strategies have been developed that aim to prevent or reduce gastrointestinal colonization and thereby to prevent pneumonia. Acid-independent stress ulcer prophylaxis and selective digestive decontamination are among those most widely discussed. There is strong evidence now that in general, drugs that alter the gastric pH (eg, antacids, H2-antagonists) facilitate respiratory tract infections in patients ventilated for more than 3 days, as compared with sucralfate, which does not. pH-independent stress ulcer prophylaxis can be considered as a physiologic approach, however limited, for the prevention of nosocomial infections, whereas selective digestive decontamination is a much more aggressive approach with potentially greater efficacy, but also clinically relevant side effects. Selective digestive decontamination effectively prevents gram-negative respiratory infections, although the major effect seems to be on tracheobronchitis and not on pneumonia. The implementation of intravenous antibiotics to oropharyngeal and intestinal decontamination seems to be an essential component for achieving full efficacy. Resistance has now become a problem at least in some hospitals, with methicillin-resistantStaphylococcus aureusstrains being the most important problem. The lack of cost-effectiveness in many countries and the growing problem of resistance are significant objections against the widespread use of selective digestive decontamination. If stress ulcer prophylaxis is achieved with sucralfate, only specific subgroups of patients still benefit from selective digestive decontamination. However, intestinal decontamination should be administered 2 hours prior to sucralfate to avoid antibiotic inactivation.