H. pylori is probably the most prevalent human pathogen worldwide. Since it was initially suggested in 1983 by Marshall and Warren to be implicated in gastritis and peptic ulcer disease, H. pylori has also been implicated in gastric carcinoma and was classified as a class I carcinogen. In the last two decades, a noteworthy body of research has revealed the multiple processes that this gram negative bacterium activates to cause gastroduodenal disease in humans. Most infections are acquired early in life and may persist for the life of the individual. While infected individuals mount an inflammatory response that becomes chronic, along with a detectable adaptive immune response, these responses are ineffective in clearing the infection. H. pylori has unique features that allow it to reside within the harsh conditions of the gastric environment, and also to evade the host immune response. In this review, we discuss the various virulence factors expressed by this bacterium and how they interact with the host epithelium to influence pathogenesis.