Abstract: Helicobacter pylori (H. pylori) is a Gram-negative spiral bacterium that colonizes gastric mucosa. Persistent infection with H. pylori is considered a major risk factor for the development of gastric cancer and is implicated in approximately 80% of cases. Globally, only 1%–2% of patients with H. pylori infection go on to develop gastric cancer, indicating that the complex interactions among H. pylori, host genetic background, and environmental factors promote gastric carcinogenesis. However, the underlying mechanisms are yet to be fully defined. Additionally, H. pylori can reshape the immune microenvironment of the stomach, which probably influences the efficacy of immunotherapy. Finally, the clinical practices to eradicate H. pylori infection face several challenges. This review will discuss the latest advances in understanding the molecular underpinnings of H. pylori involvement in the initiation, progression, and immunity of gastric cancer, as well as the issues arising in the treatment of H. pylori infection.