Cancers of the esophagus and gastroesophageal junction (GEJ) are associated with a high mortality rate. In the United States, the incidence of adenocarcinoma of the distal esophagus and GEJ is rising at an alarming rate. Decades of investigation have established the impact on survival of neoadjuvant platinum-based chemotherapy as well as chemoradiation for locally advanced tumors. Distant recurrence remains the most common pattern of failure and efforts to improve therapeutic outcome should focus on optimizing systemic therapy. Induction chemotherapy before preoperative chemoradiation and postoperative adjuvant chemotherapy are approaches to intensify systemic therapy delivery and deserve further investigation. The integration of targeted therapies and development of predictive biomarkers to identify subgroups of patients who are likely to benefit will mark the future of neoadjuvant treatment in this disease.