Advanced gastroesophageal cancer patients are often treated with systemic combination chemotherapy. The V-325 study demonstrated that adding docetaxel (D) to a frequently used regimen of cisplatin and 5-fluorouracil (CF) provided benefits with regard to overall survival, response rate, time-to-disease progression, clinical benefit, and health-related quality of life. Although the DCF regimen provides these advantages, it is accompanied by an increase in toxicity compared with the doublet regimen. The toxicity profile of DCF is acceptable only with appropriately selected patients and comprehensive toxicity management strategies. The objective of the current review was to identify trials that investigated modifications to the original DCF regimen to improve its toxicity profile and summarize response rate and toxicities. An attempt was also made to summarize ongoing modifications of the DCF regimen. MEDLINE, major meeting proceedings, and the government clinical trials website were searched until 2007. The modified DCF regimens appear to improve the toxicity profile when compared with the original DCF regimen. The docetaxel-based triplet combinations appear to have a higher response rate than the doublet combinations. Many institutions and cooperative groups continue to study docetaxel-based modifications of the DCF regimen to treat patients with gastroesophageal carcinoma. However, although modified DCF reduces the frequency of severe toxicities previously reported with DCF, considerably more advances are needed to improve the safety, survival, and convenience of patients with advanced gastroesophageal cancer. Cancer 2008. © 2008 American Cancer Society.