The human gastric pathogen Helicobacterpylori infects the human gastric mucus layer of approximately half of the world's population. Colonization with this bacterium results in superficial gastritis without clinical symptoms, but can progress into gastric or duodenal ulcers, gastric malignancies and mucosa-associated lymphoid tissue-lymphomas. Disease outcome is affected by a complex interplay between host, environmental and bacterial factors. Irrespective of disease outcome, the majority of H. pylori infected individuals remain colonized for life. Changing conditions in the human gastric mucosa may alter gene expression and/or result in the outgrowth of more fit H. pylori variants. As such, H. pylori is a highly flexible organism that is optimally adapted to its host. the heterogeneity in H. pylori populations make predictions on H. pylori-related pathogenesis difficult. In this review, we discuss host, environmental and bacterial factors that are important in disease progression. Moreover, H. pylori adaptive mechanisms, which allow its life-long survival and growth in the gastric mucosa are considered.