Objective: To review current challenges in the management of peptic ulcer disease. Methods: Review of the literature. Results: Peptic ulcer disease affects 5% to 10% of the population worldwide, with recent decreases in lifetime prevalence in high-income countries. Helicobacter pylori infection and nonsteroidal anti-inflammatory drug (NSAID) use are the most important drivers of peptic ulcer disease. Current management strategies for peptic ulcer disease focus on ulcer healing; management of complications such as bleeding, perforation, and obstruction; and prevention of ulcer recurrence. Proton pump inhibitors (PPIs) are the cornerstone of medical therapy for peptic ulcers, and complement testing for and treatment of H. pylori infection as well as elimination of NSAID use. Although advances have been made in the medical and endoscopic treatment of peptic ulcer disease and the management of ulcer complications, such as bleeding and obstruction, challenges remain. Conclusion: Peptic ulcer disease is a common health problem globally, with persistent challenges related to refractory ulcers, antiplatelet and anticoagulant use, and continued bleeding in the face of endoscopic therapy. These challenges should be met with PPI therapy of adequate frequency and duration, vigilant attention to and treatment of ulcer etiology, evidence-based handling of antiplatelet and anticoagulant medications, and utilization of novel endoscopic tools to obtain improved clinical outcomes.