Helicobacterpylori causes persistent inflammation in the human stomach, yet only a minority of persons harboring this organism develop peptic ulcer disease or gastric malignancy. H. pylori isolates possess substantial phenotypic and genotypic diversity, which may engender differential host inflammatory responses that influence clinical outcome. For example, strains that possess the cag pathogenicity island induce more severe gastritis and augment the risk for developing peptic ulcer disease and distal gastric cancer. However, important geographic differences in susceptibility to disease exist as clear-cut markers for H. pylori strains that affect certain groups of colonized individuals have little or no predictive power for other populations. Recent investigations that have more precisely delineated mechanisms of H. pylori pathogenesis will ultimately help to define which colonized persons bear the highest risk for subsequent development of clinical disease, and thus enable physicians to appropriately focus diagnostic testing and eradication therapy. Although stratification of disease risk based on H. pylori strain characteristics is unlikely to completely account for differences in clinical outcomes, it is an important first step in helping to understand the biology of long-term interactions between H. pylori and its human host.