Helicobacter pylori infects approximately half the world's population and is especially prevalent in the developing world. H. pylori is an important cause of global ill health due to its known etiological role in peptic ulcer disease, dyspepsia, gastric cancer, lymphoma, and more recently, recognized in iron deficiency anemia and idiopathic thrombocytopenic purpura. Increased antibiotic usage worldwide has led to antibiotic resistance among many bacteria, including H. pylori, resulting in falling success rates of first-line anti-H. pylori therapies. Eradication failures are principally due to resistance to clarithromycin, levofloxacin, and metronidazole. Several new treatment options or modifications of established regimens are now recommended by updated practice guidelines for primary or secondary therapy. Because these updated recommendations were published in the gastroenterological literature, internists and primary care physicians, who commonly manage H. pylori, may be unaware of these advances. In this review, we outline the changing epidemiology of H. pylori, advise on diagnostic test selection for patients not undergoing endoscopy, and highlight current management options in this era of growing antibacterial resistance.