Gastric and gastroesophageal adenocarcinoma (GGA) are significant worldwide health problems. With most patients presenting with advanced disease, palliative chemotherapy plays a significant role in treatment. Results from recent phase III studies of cytotoxic agents in combination therapy, such as docetaxel, oxaliplatin, irinotecan, capecitabine, and S-1, have been encouraging and provide patients with additional therapeutic options. Although these forthcoming regimens have allowed for more flexible patient-tailored therapy, survival continues to be suboptimal. Although still in its infancy, targeted biotherapy, including inhibitors of the vascular endothelial and epidermal growth factor receptors, seems to be promising and its incorporation into the next generation of clinical trials will hopefully improve outcomes and help advance future treatments. This article reviews current active chemotherapeutic regimens and explores the role of novel targeted therapies in advanced GGA.