Despite all recent treatment advances and the worldwide decline in the incidence rate, gastric cancer (GC) remains an ongoing global health challenge and one of the major leading causes of cancer-specific deaths, particularly in high-incidence regions including Iran. Since GC is often diagnosed in advanced stages, the best action may be to enable early diagnosis of the disease or even prevent it in the first place through identification and control of the underlying risk factors. Endoscopy, as the gold standard method, is both expensive and invasive, making it an unfavorable device in this regard. Therefore, it is crucial to implement a reliable region-specific screening and surveillance program to identify high-risk individuals with more efficient screening modalities. Here, in addition to a review of current GC knowledge, we presented the data of newly-established Population-based Cancer Registries (PBCRs) in Iran. Our assessment confirmed earlier reports of a very high GC incidence rate in the northwestern and northern provinces of Iran, most notably Ardabil. Along with the important role of conventional risk factors such as Helicobacter pylori (HP) infection and high dietary intake of salt, of more interest, we highlighted new region-specific risk factors, namely hookah, and opium. In conclusion, it seems the best results in reducing GC incidence and mortality rates on larger scales arise from modifying behavioral and environmental risk factors and advancing genetic and molecular biomarkers in order to supersede endoscopy. Regular endoscopic screening and antibiotic chemoprophylaxis against HP are still more appropriate in high-risk groups with specified criteria.