Irinotecan (CPT-11 [Camptosar]), an active agent in the treatment of fluorouacil-refractory colorectal cancer, has antitumor activity in upper gastrointestinal cancers. Clinical trials from Japan indicate antitumor responses in gastric and pancreatic cancers. Cisplatin (Platinol), a central agent in the treatment of upper gastrointestinal malignancies, is a logical drug to study in combination with irinotecan in upper gastrointestinal cancers. In vitro studies have shown important sequence-dependent synergy of cisplatin/irinotecan combination therapy. Irinotecan appears to prevent removal of cisplatin-induced DNA-interstrand cross-links. Initial phase I and III trials of cisplatin plus irinotecan appear to confirm this synergy, with Japanese trials in gastric cancer showing an encouraging rate of response with acceptable toxicity. A phase I trial conducted at Memorial Sloan-Kettering Cancer Center has demonstrated the safety and tolerability of weekly cisplatin and irinotecan. Currently, a phase II trial of this weekly regimen is under way in patients with metastatic or recurrent esophageal cancer. The response proportion compares favorably to standard therapy, with relatively mild toxicity. Other phase II studies, including single-agent irinotecan in esophageal cancer and the combination of cisplatin and irinotecan in gastric cancer, are being initiated at other US institutions.