Helicobacter pylori is an important bacterial pathogen of humans. It infects more than one half of the human population, usually during childhood, and establishes a chronic and often lifelong infection 1, 2. H. pylori infection invariably induces a chronic inflammatory response of the gastric mucosa. Infections can remain asymptomatic or progress to symptomatic diseases that include gastroduodenal ulcer disease, gastric adenocarcinoma, and gastric lymphoma of the mucosa-associated lymphoid tissue lymphoma 2, 3. H. pylori has been recognized as a Class I human carcinogen since the early 1990s [4], and is etiologically responsible for approx. new 900 000 cases of gastric cancer per year, a substantial proportion of all human cancers [5].

H. pylori is a bacterial species with an exceptional degree of genetic diversity and variability. It was acquired by humans in Africa around 100 000 years ago 6, 7, and has accompanied modern humans during multiple ancient and more recent migrations out of Africa 6, 8, 9•. In present times, the common and complex history of humans and H. pylori is now reflected by a highly distinctive phylogeographic population structure 7, 8, 10, 11, 12. The exceptionally high allelic diversity of H. pylori results from the combination of a very high mutation rate and a highly efficient DNA uptake and recombination machinery enabling DNA exchange between different H. pylori strains during mixed infections 13, 14, 15•. Potential roles of other genetic elements in creating genomic diversity, such as commonly occurring prophages and insertion sequences [16], remain to be elucidated. The molecular mechanisms responsible for this unique genetic plasticity of H. pylori and the contribution of H. pylori genome variation to its success as a global pathogen are the major topics of this review article, which summarizes the most important developments in this field in the last decade.