One of every 4 to 5 patients who receives antimicrobial therapy for Helicobacter pylori will not have successful eradication. Antimicrobial resistance, poor compliance with the antibiotic regimen, and drug-related side effects all play a role in determining the outcome of therapy. This article discusses the issues involved in H. pylori eradication, the mechanism of antibiotic delivery to the mucus layer of the stomach, and primary and secondary treatment strategies for H. pylori in the United States.