Many changes have occurred over the last three decades in the field of stress ulcer gastrointestinal bleeding and its prevention. The topic is controversial, fuelled by disparate data, studies at risk of bias, and the impression that the problem is not as serious as it once was. Indeed, compared with over four decades ago when mucosal ulceration of the stomach causing serious bleeding was first described, a relatively small proportion of critically-ill patients now develop clinically important bleeding. Acid suppression is commonly prescribed for stress ulcer prophylaxis (SUP), targeting subgroups of patients at high risk in the intensive care unit (ICU), rather than universal prevention. The randomized clinical trials to date suggest a significant reduction in CIB with use of histamine-2-receptor antagonists (H2RAs) compared with no SUP, with no impact on pneumonia, ICU mortality, or length of stay. However, these trials are of moderate quality. More recent RCTs suggest proton pump inhibitors compared with H2RAs may significantly reduce the risk of CIB without influencing the risk of pneumonia, ICU mortality, or length of stay. These trials are also of moderate quality. Today, the decision whether to use SUP, and which agent to use, is complex. Clinical considerations include local epidemiological data (for centres documenting these outcomes), and patient-specific risks of gastrointestinal bleeding and infection, indexed to case mix.