Gastric cancer, though not among the top 10 malignancies in the United States, remains a significant cause of cancer death globally. The biological differences between Eastern and Western tumors complicate standard-of-care therapy selection. Multidisciplinary treatment, including systemic chemotherapy, radiotherapy, surgery, immunotherapy, and targeted therapy, is crucial. Triplet chemotherapy for resectable gastric cancer is now widely accepted, and molecular subtypes are guiding personalized therapy. Biomarkers such as microsatellite instability (MSI), programmed cell death ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutation burden, and Epstein-Barr virus are increasingly influencing systemic therapy approaches. Research remains focused on less differentiated histologic subtypes and those without markers of immunotherapy activity. Diagnosis and staging involve endoscopy, imaging, and staging laparoscopy, with MSI testing becoming a critical component. Management of localized disease includes perioperative and adjuvant chemotherapy, with preoperative therapy gaining preference due to improved outcomes. Immunotherapy, particularly with PD-1/PD-L1 inhibitors, has shown promise, especially in MSI-high tumors. Tumor mutation burden (TMB) and HER2 positivity are also emerging as important biomarkers. Antiangiogenic therapy, such as ramucirumab, has demonstrated survival benefits. Novel approaches, including heated intraperitoneal chemotherapy (HIPEC) and circulating tumor DNA (ctDNA) monitoring, are being explored to improve outcomes and detect recurrence.Gastric cancer, though not among the top 10 malignancies in the United States, remains a significant cause of cancer death globally. The biological differences between Eastern and Western tumors complicate standard-of-care therapy selection. Multidisciplinary treatment, including systemic chemotherapy, radiotherapy, surgery, immunotherapy, and targeted therapy, is crucial. Triplet chemotherapy for resectable gastric cancer is now widely accepted, and molecular subtypes are guiding personalized therapy. Biomarkers such as microsatellite instability (MSI), programmed cell death ligand 1 (PD-L1), human epidermal growth factor receptor 2 (HER2), tumor mutation burden, and Epstein-Barr virus are increasingly influencing systemic therapy approaches. Research remains focused on less differentiated histologic subtypes and those without markers of immunotherapy activity. Diagnosis and staging involve endoscopy, imaging, and staging laparoscopy, with MSI testing becoming a critical component. Management of localized disease includes perioperative and adjuvant chemotherapy, with preoperative therapy gaining preference due to improved outcomes. Immunotherapy, particularly with PD-1/PD-L1 inhibitors, has shown promise, especially in MSI-high tumors. Tumor mutation burden (TMB) and HER2 positivity are also emerging as important biomarkers. Antiangiogenic therapy, such as ramucirumab, has demonstrated survival benefits. Novel approaches, including heated intraperitoneal chemotherapy (HIPEC) and circulating tumor DNA (ctDNA) monitoring, are being explored to improve outcomes and detect recurrence.