Helicobacter pylori causes persistent infection and inflammation in the human stomach, yet only a small fraction of persons harboring this organism develop peptic ulcer disease. An important question is why this variation in infection outcome exists. Recent studies have demonstrated that H pylori isolates possess substantial phenotypic and genotypic diversity that may engender differential host inflammatory responses that influence clinical outcome. Further investigation in this field may help to define which H pylori-infected persons bear the highest risk for subsequent development of peptic ulcer disease, and thus enable physicians to focus eradication therapy.