Novel strategies are needed to control infection with Helicobacter pylori. Prophylactic and therapeutic immunization against this gastric pathogen is possible in animal models, and initial human studies in H. pylori-infected subjects showed that immunization with H. pylori urease is both safe and immunogenic. In rodents, gastric protection against Helicobacter species infection does not depend on the humoral immune response, and a prominent role of the major histocompatibility complex II-restricted CD4(+) T-cell response is recognized; however, much remains to be learned about the mechanisms of effective bactericidal response. A clear understanding of the basic mechanisms of gastric immune protection in humans is of the utmost importance for the development of an effective human vaccine. More potent vaccines are likely to be required to induce protection in humans. The availability of two complete genome sequences of H. pylori represents a unique opportunity to identify novel vaccine antigens. Multivalent vaccines delivered by recombinant attenuated bacteria or administered with nontoxic adjuvants need to be evaluated in relevant models.