Helicobacter pylori, a Gram-negative flagellate bacterium that infects the stomach of more than half of the global population, is regarded as the leading cause of chronic gastritis, peptic ulcer disease, and even gastric adenocarcinoma in some individuals. Although the bacterium induces strong humoral and cellular immune responses, it can persist in the host for decades. It has several virulence factors, some of them having vaccine potential as judged by immunoproteomic analysis. A few vaccination studies involving a small number of infected or uninfected humans with various H. pylori formulations such as the recombinant urease, killed whole cells, and live Salmonella vectors presenting the subunit antigens have not provided satisfactory results. One trial that used the recombinant H. pylori urease coadministered with native Escherichia coli enterotoxin (LT) demonstrated a reduction of H. pylori load in infected participants. Although extensive studies in the mouse model have demonstrated the feasibility of both therapeutic and prophylactic immunizations, the mechanism of vaccine-induced protection is poorly understood as several factors such as immunoglobulin and various cytokines do not contribute to protection. Transcriptome analyses in mice have indicated the role of nonclassical immune factors in vaccine-induced protection. The role of regulatory T cells in the persistence of H. pylori infection has also been suggested. A recently developed experimental H. pylori infection model in humans may be used for testing several new adjuvants and vaccine delivery systems that have been currently obtained. The use of vaccines with appropriate immunogens, routes of immunization, and adjuvants along with a better understanding of the mechanism of immune protection may provide more favorable results.