The discovery of Helicobacter pylori and subsequent research efforts have led to a fundamental change in our understanding of several gastric and extra-gastric diseases, including cancer.

Chronic Helicobacter pylori infection is an etiological factor in non-cardia gastric cancer and most cases of low-grade mucosa-associated lymphoid tissue (MALT) lymphoma. However, there is an inverse association of Helicobacter pylori infection with other gastric malignancies, such as esophageal adenocarcinoma, cardia gastric cancer, and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). The possible role of Helicobacter spp. in pancreatic and colorectal cancers has been a subject of intensive research. Indication for the eradication of Helicobacter pylori must now be considered with caution on an individual basis of personalized medicine.

This paper provides a thorough review of the relevance of Helicobacter spp. in esophageal adenocarcinoma, gastric cancer and lymphoma, hepatobiliary malignant tumors, pancreatic ductal adenocarcinoma, and intestinal malignancies. Environmental factors, gastrointestinal niches, and possible perspectives are also discussed.

In the face of the continuously decreasing chronic Helicobacter pylori infection worldwide, it is necessary to accept that this phenomenon has not yet been fully clarified. There may be fundamental changes of “modern times” that could be responsible for the gradual disappearance of Helicobacter spp. from the human microbiome.