Helicobacter pylori, the etiologic agent of gastritis and peptic ulceration, may infect the gastric mucosa of over half of the world's population. Despite the high infection rate, symptomatic disease beyond gastritis (characterized by gastric or duodenal ulcer) is noted in a small, but nevertheless significant, fraction of this population. What defines an H. pylori strain as a pathogen that can cause the more serious clinical manifestations? In addition to the more well recognized virulence determinants, such as urease, flagella, and vacuolating cytotoxin, evidence is emerging that the more virulent strains possess well defined segments of DNA. These "pathogenicity islands" include cytotoxin-associated gene A and encode proteins involved in signal transduction events that may facilitate intimate attachment to host cells, cytoskeletal rearrangement via actin polymerization, and host cell protein phosphorylation.