Stress-related mucosal disease in the critically ill population can lead to clinically important gastrointestinal bleeding (CIB). Reported risk factors for the development of CIB include but are not limited to invasive mechanical ventilation for greater than 48 hours, coagulopathy, and multiorgan failure. Gastric acid suppressive therapy is prescribed in critically ill patients for stress ulcer prophylaxis (SUP), most often proton pump inhibitors but also histamine-2 receptor antagonists. However, the use of SUP is not without risk and has been associated with Clostridium difficile infection and pneumonia. Factors inherent to malignancy and/or malignancy treatment may pose additional risk for CIB as well as infection. This chapter will provide an evidence-based review of SUP as well as considerations in the critically ill oncology population.