The increasingly prevalent use of antithrombotic drug combinations and an aging population are resulting in growing rates of gastrointestinal bleeding (GIB). GIB is a serious condition in the setting of stable and acute coronary syndromes, associated with high rates of ischemic events. Physicians should be aware of GIB in high-risk populations, especially the elderly and patients with anemia. We discuss the risk of GIB in patients treated with different antiplatelet and antithrombotic medications and their combinations, factors associated with GIB, and its optimal management and prevention.