Stress-induced gastrointestinal bleeding is associated with increased morbidity and mortality in critically ill patients. Within the past few decades, the incidence of stress-induced gastrointestinal bleeding has decreased. Prophylaxis of stress-induced gastrointestinal bleeding, which is aimed at preventing morbidity and mortality, has to be achieved with as few adverse effects as possible. Data indicate that not all critically ill patients need prophylaxis for stress-induced gastrointestinal bleeding. The main risk factors associated with clinically important hemorrhage are mechanical ventilation for >48 h, and coagulopathy (thrombocyte count <50/nl, partial thromboplastin time (PTT) >2 times the upper limit of the normal range, international normalized ratio (INR) >1.5). Ranitidine is more effective than sucralfate for the prevention of clinically important bleeding. Immediate-release omeprazole is as effective as cimetidine, and is more efficient at increasing the intragastric pH. As yet, however, there is no firm evidence that any of the drugs used for prophylaxis of stress-induced gastrointestinal bleeding in critically ill patients decrease mortality or the length of hospital stay. When to stop prophylaxis is decided on clinical grounds rather than on the basis of data from clinical studies.