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Gastric cancer (GC) remains a significant concern worldwide, with a very high incidence in Japan, South Korea, and China. Early diagnosis of GC is important for reducing its mortality; to achieve this, screening of individuals at a high risk for developing GC should include frequent esophagogastroduodenoscopy. Currently, various population-based GC screening strategies are being implemented in South Korea, Japan, and the Matsu region of Taiwan. Many studies have suggested that serum pepsinogens (sPGs) can be used as GC biomarkers in South Korea, China, Europe, and other countries; indeed, Japan first included the sPG test in GC screening prior to 1990. However, while the role of sPGs (particularly type 1) as a marker of atrophic gastritis is well known, studies on the association between sPG levels and GC have mainly focused on the association with intestinal-type GC. Recent studies have demonstrated that sPGII is associated with severe inflammation and proliferation. Specifically, high sPGII levels and Helicobacter pylori positivity are associated with an increased risk of early diffuse-type GC, particularly in young females. In this review, the physiology of sPGs and the usefulness of sPG levels in the detection of intestinal- or diffuse-type GC are discussed in terms of sex and age.