Helicobacter pylori is a Gram-negative, spiral bacterium that colonizes the gastric mucosa of at least 50% of the world's population and plays a causative role in the development of chronic gastritis as well as in gastric and duodenal ulcers. H. pylori triggers vigorous humoral and cellular immune responses in both systemic and mucosal compartments. In spite of this response, the vast majority of infected hosts are unable to clear the infection, and it persists for decades. Although Helicobacter is tolerated by a naive host organism, preclinical studies have demonstrated that prophylactic or therapeutic vaccinations efficiently clear Helicobacter from the stomach. The understanding of the mechanisms leading to the Helicobacter persistence or the vaccine-induced eradication of Helicobacter in animal models will help to define optimal immunization strategies for future anti-Helicobacter vaccination clinical trials.