Helicobacter pylori infection is the most common chronic bacterial infection worldwide and is associated with divergent clinical outcomes that range from simple asymptomatic gastritis to more serious conditions, such as peptic ulcer disease and gastric cancer. The key determinants of these outcomes are the severity and distribution of H. pylori-induced gastritis. Host genetic factors play an important role in influencing disease risk, but identifying candidate genes is a major challenge that has to stem from a profound understanding of the pathophysiology of the disease. In the case of H. pylori, the most promising candidate genes are ones that attenuate gastric acid secretion and lead to a destructive chronic inflammatory response against the infection. In particular, certain cytokine and innate immune response gene polymorphisms appear to influence risk of gastric cancer and its precursor conditions. There are currently no convincing genetic risk markers for acquisition of H. pylori infection or risk of developing peptic ulcer disease. Future research agendas should focus on identifying the full genetic risk profile for H. pylori-induced gastric neoplasia. This will help to target the population most at risk by directing eradication therapy and closer follow-up to the affected individuals.