Cancers of the esophagus arise as adenocarcinomas and squamous cell carcinomas; these represent distinct diseases, with differing prognosis, yet they are often studied in common trials. With surgery alone, 5 year survival for T2-T3N0 disease is less than 30% to 40%, and declines to less than 25% with nodal involvement. The CROSS randomly assigned patients to surgery alone or to weekly carboplatin/paclitaxel X 5 and 41.4 Gy concurrent radiotherapy, followed by surgery. Seventy-five percent of enrolled patients had adenocarcinoma. Preoperative combined-modality therapy improved R0 resection from 69% to 92% (p < 0.001 and improved median survival from 24 months to 49.4 months (p < 0.003). This regimen reduced both locoregional recurrence (34% to 14%; p < 0.001) and the development of peritoneal carcinomatosis (14% to 4%; p < 0.001). Systemic perioperative therapy may have a greater effect on distant disease, the predominant mode of failure for these patients, and current trials compare preoperative chemoradiation with periooperative systemic therapy. PET scan response during preoperative chemotherapy without radiotherapy correlates with improvements in pathologic response and with improved survival. Nonresponse on early PET scan allows identifıcation of patients for earlier surgery and discontinuation of ineffective preoperative chemotherapy, without survival detriment. There is no predictive benefıt for early PET scan during the course of chemotherapy followed by chemoradiotherapy. The use of early PET scan during induction chemotherapy is being evaluated in CALGB/Alliance trial (NCT01333033). Molecular profıling has identifıed somatic gene mutations and pathways that may be oncogenic in upper gastrointestinal cancers. Potential targets include the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), HER2, mammalian target of rapamycin (mTOR), fıbroblast growth factor receptor (FGFR), MEK, and others. Targeted therapies with known survival benefit in esophagogastric cancer are currently limited to trastuzumab for HER2 overexpressing cancers, or ramicirumab.