Gastrointestinal tumors are very frequent. The main therapy for gastric and gastroesophageal junction (GEJ) carcinomas is surgical resection, but the prognosis of advanced/metastatic cases remains dismal. Recent insights into the molecular basis of gastric/GEJ carcinomas have changed the management of these tumors. The results of the Trastuzumab for Gastric Cancer (TOGA) trial led to the use of anti-human epidermal growth factor receptor 2 (HER2) drugs for gastric/GEJ carcinomas with HER2 overexpression. More recently, immune therapy based on anti-PD1/PDL1 drugs has also become a therapeutic option for these patients based on immunohistochemical detection of PDL1 expression in the tumor, measured with the combined positivity score (CPS) and also on the expression of the proteins encoded by mismatch repair genes. The most recent and promising innovation in gastric and GEJ carcinomas has been the introduction of drugs targeting claudin 18.2. Although fibroblast growth factor receptor 2 is more frequently altered in gastric carcinoma/GEJ carcinomas, abnormalities in fibroblast growth factor receptor 3 lead to tumor growth and therapy resistance and can be targeted. It is therefore expected that in the future, anti-FGFR drugs might also enter the therapeutic armamentarium for these tumors. Pancreatobiliary carcinoma remains as one of the most lethal human tumors. Surgical resection is the only curative option, but many patients are diagnosed at advanced or metastatic stages, not amenable to surgery. Response to chemotherapy is not optimal and the targeted therapies have not evolved much. Molecular abnormalities of pancreatobiliary tumors are varied, and not all are targetable. Next-generation sequencing (NGS) is indicated for these lesions, as any potentially targetable abnormality can be the only chance of survival for these patients.