This narrative review discusses the genetics of protection against Helicobacter pylori (Hp) infection . After a brief overview of the importance of studying infectious disease genes, we provide a detailed account of the properties of Hp, with a view to those relevant for our topic . Hp displays a very high level of genetic diversity, detectable even between single colonies from the same patient . The high genetic diversity of Hp can be evaded by stratifying patients according to the infecting Hp 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 MyD88, TIRAP, and IL1RL1 against Hp 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 (TREGS).