Helicobacter pylori affect around 50% of the population worldwide. More importantly, the gastric infection induced by this bacterium is deemed to be associated with the progression of distal gastric carcinoma and gastric mucosal lymphoma in the human. H. pylori infection and its prevalent genotype significantly differ across various geographical regions. Based on numerous virulence factors, H. pylori can target different cellular proteins to modulate the variety of inflammatory responses and initiate numerous "hits" on the gastric mucosa. Such reactions lead to serious complications, including gastritis and peptic ulceration, gastric cancer and gastric mucosa-associated lymphoid structure lymphoma. Therefore, H. pylori have been considered as the type I carcinogen by the Global Firm for Research on Cancer. During the two past decades, different reports revealed that H. pylori possess oncogenic potentials in the gastric mucosa through a complicated interplay between the bacterial factors, various facets, and the environmental factors. Accordingly, numerous signaling pathways could be triggered in the development of gastrointestinal diseases (e.g., gastric cancer). Therefore, the main strategy for the treatment of gastric cancer is controlling the disease far before its onset using preventive/curative vaccination. Increasing the efficiency of vaccines may be achieved by new trials of vaccine modalities, which is used to optimize the cellular immunity. Taken all, H. pylori infection may impose severe complications, for resolving of which extensive researches are essential in terms of immune responses to H. pylori. We envision that H. pylori-mediated diseases can be controlled by advanced vaccines and immunotherapies.