Stress ulcer prophylaxis (SUP) is regarded as standard of care in the intensive care unit (ICU). However, recent randomized, clinical trials (RCTs) and meta-analyses have questioned the rationale and level of evidence for this recommendation. The aim of the present systematic review was to evaluate if SUP in the critically ill patients is indicated. Data sources: MEDLINE including MeSH, EMBASE, and the Cochrane Library. Participants: patients in the ICU. Interventions: pharmacological and non-pharmacological SUP. Study appraisal and synthesis methods: Risk of bias was assessed according to Grading of Recommendations Assessment, Development, and Evaluation, and risk of random errors in cumulative meta-analyses was assessed with trial sequential analysis. A total of 57 studies were included in the review. The literature on SUP in the ICU includes limited trial data and methodological weak studies. The reported incidence of gastrointestinal (GI) bleeding varies considerably. Data on the incidence and severity of GI bleeding in general ICUs in the developed world as of today are lacking. The best intervention for SUP is yet to be settled by balancing efficacy and harm. In essence, it is unresolved if intensive care patients benefit overall from SUP. The following clinically research questions are unanswered: (1) What is the incidence of GI bleeding, and which interventions are used for SUP in general ICUs today?; (2) Which criteria are used to prescribe SUP?; (3) What is the best SUP intervention?; (4) Do intensive care patients benefit from SUP with proton pump inhibitors as compared with other SUP interventions? Systematic reviews of possible interventions and well-powered observational studies and RCTs are needed.