Helicobacter pylori is a Gram-negative bacterium which has exquisitely adapted to survive in the acidic, hostile environment of the stomach. H. pylori is extremely motile and is found in the mucus layer lining the stomach. By penetrating this thick mucus layer, the bacteria can attach to gastric epithelial cells, thus avoiding being ‘washed’ through the stomach. H. pylori infection tends to persist for the life of the host and, with more than half the population of the world being infected, it is not surprising that H. pylori strains have co-evolved with Homo sapiens. For this reason, and due to several cunning adaptations, the bacteria are able to induce low-level inflammation to gain access to the nutrients required for them to grow and survive, but simultaneously evade host immune responses. Importantly, H. pylori is presently the only bacterial species classified as a type 1 carcinogen by the World Health Organization (WHO) and remains a significant cause of morbidity and mortality worldwide. Approximately one in five infected individuals develop disease, including either peptic ulcer disease, gastric mucosal-associated lymphoid tissue lymphoma and, in the worst case (approximately 1–2% of infected individuals), gastric adenocarcinoma. Gastric cancer remains the second leading cause of death from malignancy worldwide and, with H. pylori being a major cause, it is clear that H. pylori infection still has a major impact on the global disease burden. Clearly there is a need to develop novel therapies and, ideally, a highly efficacious vaccine, based on a sound understanding of H. pylori and its interplay with the human host. This review will summarize recent findings in the context of host–pathogen interactions and modulation of inflammation as well as highlighting recent advances in vaccine development.Every, A.L (2013) Key host–pathogen interactions for designing novel interventions against Helicobacter pylori Trends in Microbiology, 21, 253–259.