Use of acid-suppressive therapy (AST) to prevent stress gastropathy in the intensive care unit has grown rapidly over the past 20 years. The primary indications for such use of AST include need for mechanical ventilation, overt gastrointestinal bleeding, severe burn, and head trauma. Despite this limited list of indications, proton pump inhibitors (PPIs) often are overprescribed for purposes of stress prophylaxis. Decreased mucosal blood flow with subsequent tissue ischemia is thought to be the mechanism responsible for stress-induced gastropathy. Subsequent activation of inflammatory and vasoconstrictive mediators determines the severity of the gastropathy. Numerous basic science studies suggest that enteral nutrition (EN) can improve mucosal blood flow and reverse the generation of these inflammatory mediators. Clinical studies evaluating the effectiveness of EN vs acid-suppressive medications, however, have shown variable results (and there are no randomized controlled trials to date). In hypersecretory states (such as head trauma and burns), AST should be given, even in patients who are tolerating EN. In the absence of a hypersecretory state, pharmacologic AST may be avoided or discontinued in patients who are tolerating EN. Stress prophylaxis medications also should be discontinued in patients who do not have a clear indication for their use. Overt bleeding in a patient receiving EN for stress prophylaxis should prompt the initiation of a PPI. Randomized controlled studies investigating the efficacy of EN for stress ulcer prophylaxis are needed. Protocols should be developed to alert healthcare teams to consider discontinuation of AST, especially when tolerance of EN is achieved.