The evolution of drug-eluting stents (DES), effective periprocedural antithrombotic therapy, and advanced interventional techniques have fueled the surge of percutaneous coronary interventions. Stent thrombosis remains a serious complication of coronary artery stent implantation. Long-term antiplatelet therapy is required to prevent stent thrombosis, especially following DES implantation. Discontinuation of antiplatelet therapy (particularly clopidogrel) is the strongest independent risk factor for the development of stent thrombosis. Bleeding complications, most of which arise from the upper gastrointestinal (GI) tract, are the major limiting factors for antiplatelet therapy. The association of aspirin with the increased risk of upper GI bleeding has been well established. Peptic ulcer bleeding and Helicobacter pylori infection are the 2 most important risk factors for aspirin-associated GI bleeding complications. Endoscopy (for both surveillance and potential intervention), performed either emergently or semielectively, is the primary tool for definitive management of GI bleeding. Considering the increase in GI bleeding risk seen with prolonged antiplatelet therapy, adjunctive proton pump inhibitor therapy and/or eradication of H. pylori infection might be beneficial for DES patients on long-term antiplatelet therapy.