The treatment of esophagogastric cancer has been rapidly evolving in the past decade. New cytotoxic drugs and targeted agents have been integrated in the therapeutic paradigm. To better understand the tumor biology and to better utilize targeted agents, genetic alterations in esophagogastric cancer have been actively explored. For example, Her2/Neu amplification and expression were observed in gastric and gastroesophageal (GE) junction cancers. Combination of trastuzumab with cytotoxic chemotherapy has demonstrated a survival advantage in patients with Her2/Neu positive gastric cancer. However, the prognosis of advanced esophagogastric cancer remains poor. This is largely attributed to the tumor heterogeneity and poorly understood tumor biology. This article provides a summary of potential genetic targets and the role of novel targeted agents in the treatment of esophagogastric cancer.