Effective locoregional treatments are needed for adenocarcinomas of the esophagus, stomach, and pancreas. Paclitaxel has been investigated as a radiation sensitizer for upper gastrointestinal malignancies. In esophageal cancer, the combination of low-dose weekly paclitaxel, platinum, and concurrent radiation therapy (RT) has substantial activity and is well tolerated. Regimens that add fluorouracil (5-FU) to paclitaxel and platinum or incorporate hyperfractionation radiation have a higher incidence of severe esophagitis. In gastric cancer, adjuvant concurrent paclitaxel, 5-FU, and radiation is being investigated in the cooperative group setting. In pancreatic cancer, paclitaxel may be a radiation sensitizer even to tumor cells that are resistant to paclitaxel as a single agent. The Radiation Therapy Oncology Group (RTOG) demonstrated a 43% 1-year survival with paclitaxel/RT for patients with locally advanced pancreatic cancer. This represented a 40% improvement in survival compared to the previous RTOG 92-09 study of 5-FU-based chemoradiation. Ongoing trials in pancreatic cancer are investigating the addition of gemcitabine to paclitaxel and radiation and incorporating molecular targeting agents.