Since Helicobacter pylori (H. pylori) is the first successful culture three decades ago, ongoing perspectives regarding the relationship between the bacterium and human health have changed radically (1, 2). Apart from tremendous studies performed during the last years, there are still many debates regarding the unclear rationale for existence of such bacteria in human stomach (3, 4). Basically, due to the beneficiary effects of H. pylori colonization (regression in child asthma and other allergic disorders), it has been concluded that H. pylori is a common flora or at least harmless bacterium (5–10), Conversely, because of the causative role of H. pylori in certain digestive diseases such as duodenal ulcer and gastric cancer, other reports are quite contradictory (11–13). A large number of discussions led to a consensus regarding presence of H. pylori in the human stomach (5, 11, 14, 15). Our knowledge about biology of H. pylori suggests that the bacterium is highly adapted to stay in gastric mucosa for long time (1, 16). Indeed, living in lower surface of gastric mucosa, with no bacterial competition, provided a novel place to survive. Moreover, H. pylori is able to multiply freely due to the protective effects by mucosal layer. Thus, H. pylori had an opportunity to thrive in stomach over the course of tens of thousands of years of co-evolution with humans (17). Additionally, the high frequency of mutation in the genome also led to higher chances of survival, and natural selection helped them to remain and cause chronic infection (18). Determining whether H. pylori is beneficial or detrimental in human stomach has been a challenging area of research in gastroenterology (5, 11, 19, 20). In this article, we aim to elucidate various aspects of this persistent colonization of this beneficial infection. H. pylori: Carried by human over the history It seems that H. pylori is an old recognized bacterium, which is not clinically comparable with new discovered infectious agents such as human immunodeficiency virus (HIV). In other words, HIV was introduced to human hosts <50 years ago. Given a long period of H. pylori colonization in the human stomach, mutual benefits obliged both partners to adapt themselves in order to establish stable symbiosis. It has been firmly established that H. pylori first subverts innate immunity and then modulates the adaptive immune system (blocking the activation of both B and T cells) (21–23). As a result, cagA and vacA, the main bacterial products, will inhibit B cell and T cell proliferation, respectively. Accordingly, immune response in the stomach is silenced against digested microbes (24, 25). Undeniably, the stomach, with its harsh acidic condition, is a container for many digested microbes every day. Possibly, regulation and modulation of immune response arose after microbial exposure to H. pylori colonizing the stomach (24, 25). Our current understanding of the strategies used by this pathogen to make a lifelong colonization, disclosed that maybe for our old ancestors having this bacteria in the stomach happened initially by accident, but due to natural selection, H. pylori made a set of adaptations, enabling the bacterium to survive and also thrive in the surface of human gastric epithelial cells. To everyone’s surprise, after millions years of living in human stomach, H. pylori became a strategic member of our microbiome (26). Undoubtedly, it is no exaggeration to say that both host and the bacterium are following a constant beneficial relationship, which is quite unique in biological world. After long period of H. pylori gastric colonization, it has evolved into a highly adaptable persistent bacterium, obtaining all necessary features of the most successful human pathogen.