H pylori is a global human pathogen and is the major cause of gastritis and the gastritis-associated diseases: gastric ulcer, duodenal ulcer, gastric cancer, and primary gastric B-cell lymphoma (MALToma). Although several reliable diagnostic tests are widely available, the ideal regimen for treating the infection re-mains to be established. The current first-line or legacy triple therapy regimens fail in 20% to 40% of patients. Causes of treatment failure include antibiotic resistance, poor compliance, short (7-10 days) duration of therapy, and drug-related side effects. Fourteen-day triple therapy has an approximately 12% better cure rate than does 7-day therapy; therefore, shorter durations can no longer be recommended. Recent studies confirmed older observations that the success rate of legacy triple regimens (PPI plus two antibiotics) can be improved if the duration is extended to 14 days or if a third antibiotic is given. Sequential therapy (PPI plus amoxicillin followed by a PPI plus clarithromycin plus metronidazole) requires further evaluation although the concept appears very promising and therapy should probably replace the legacy triple therapies. More studies are needed to examine doses, durations, and the need for sequential administration of the drugs, which extends the duration to 14 days. Nonetheless, sequential quadruple therapy probably should replace the legacy triple therapies. Classic quadruple therapy contains bismuth, a PPI, 1500 mg of metronidazole, and 1500 mg of tetracycline. It provides the highest average eradication rates and in many regions should be considered as the initial approach. Confirmation of eradication using noninvasive diagnostic tests, such as a urea breath test or stool antigen assay, is now the standard of care. The diagnosis of latent or symptomatic H pylori like the diagnosis of latent or symptomatic syphilis, always should prompt treatment. Because of decreasing cure rates, new and improved therapies are needed.