Over the past decade, a multitude of molecular targeted agents have been explored in the treatment of advanced metastatic gastric. Recent advances in molecular signaling pathways that are dysregulated in gastric cancer lead to the development of new targeted therapies for the treatment of advanced and metastatic gastric cancer. The addition of trastuzumab to first-line chemotherapy is now a standard of care for the treatment of Human epidermal growth factor receptor (HER2-) positive advanced or metastatic disease, and other HER2-targeted therapies are in late-stage clinical development. Findings from recent major clinical trials provide important insight into the future of metastatic gastric cancer management, which may include the use of anti-angiogenesis, Mesenchymal epithelial transition factor (MET) and Hedgehog Pathways Inhibitortherapy across multiple treatment lines, in the salvage setting, and as part of novel regimens in combination with other targeted agents.