Background: Carcinomas of the stomach and esophagogastric junction (EGJ) are the fifth leading cause of cancer-related deaths worldwide. In Germany, gastric cancer ranks tenth in incidence across both sexes. The new German national guideline aims to provide the most relevant evidence-based recommendations on diagnosis and treatment of gastric and EGJ adenocarcinomas and has been comprehensively updated by an interdisciplinary panel of experts from national medical societies. Summary: The updated S3 guideline reflects the latest advances in diagnostics, improved palliative therapies, and supportive care. The objectives are to improve the quality of individual and broad care and to ensure consistent, evidence-based treatment strategies. Key Messages: New recommendations introduce preventive strategies, including management of familial risk due to microsatellite instability (MSI) and H. pylori eradication. The biomarkers HER2, PD-L1, MSI, and Claudin 18.2 enable the use of targeted therapies that improve long-term outcomes in advanced disease. Combinations of chemotherapy with immunotherapy nivolumab, pembrolizumab, or tislelizumab significantly prolong survival compared with chemotherapy alone (e.g., nivolumab 14.4 vs. 11.1 months, HR 0.71; pembrolizumab 13.0 vs. 11.4 months, HR 0.75; tislelizumab 17.2 vs. 12.6 months, HR 0.74) with 5-year survival rates up to 16%. In patients with high Claudin 18.2 expression, zolbetuximab plus chemotherapy improved median survival to 16.4 vs. 13.4 months (HR 0.77). For patients in good general condition, subsequent lines of therapy including biomarker-driven approaches (trastuzumab deruxtecan, pembrolizumab) or third-line therapies (e.g., trifluridine tipiracil) and advanced molecular diagnostics are recommended after treatment failure.