This article examines the role of neoadjuvant therapy in the treatment of locally advanced esophageal adenocarcinoma. Recent studies have demonstrated that pre- or perioperative chemotherapy is associated with improved survival. Neoadjuvant chemoradiotherapy continues to be investigated but is associated with several advantages over neoadjuvant chemotherapy alone. Primary chemoradiotherapy is the accepted standard of care for medically inoperable patients, whereas adjuvant chemoradiotherapy may be considered for patients who undergo primary resection of lower esophageal/gastroesophageal junction tumors. Future directions include the investigation of newer chemotherapy regimens, the addition of targeted therapies, and the use of position emission tomography to provide an early assessment of response.