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This narrative review discusses the genetics of protection against <i>Helicobacter pylori</i> (<i>Hp</i>) infection. After a brief overview of the importance of studying infectious disease genes, we provide a detailed account of the properties of <i>Hp</i>, with a view to those relevant for our topic. <i>Hp</i> displays a very high level of genetic diversity, detectable even between single colonies from the same patient. The high genetic diversity of <i>Hp</i> can be evaded by stratifying patients according to the infecting <i>Hp</i> strain. This approach enhances the power and replication of the study. Scanning for single nucleotide polymorphisms is generally not successful since genes rarely work alone. We suggest selecting genes to study from among members of the same family, which are therefore inclined to cooperate. Further, extending the analysis to the metabolism would significantly enhance the power of the study. This combined approach displays the protective role of <i>MyD88, TIRAP,</i> and <i>IL1RL1</i> against <i>Hp</i> infection. Finally, several studies in humans have demonstrated that the blood T cell levels are under the genetic control of the CD39⁺ T regulatory cells (T_REGS).