Chemotherapy has a proven palliative role in advanced gastric cancer, significantly improving quality of life and prolonging survival compared with best supportive care alone. Although there is no standard of treatment, 5-fluorouracil (5-FU)/cisplatin doublets and the combination of epirubicin, cisplatin and 5-FU (ECF) have both achieved response rates in the range of 40–50% and median overall survival of 8–10 months. Either could claim the status of a reference regimen. Single-agent irinotecan achieved response rates (RR) of 18% and 23% in phase II studies, and 48% when combined with cisplatin. However, a randomized trial of irinotecan plus cisplatin versus irinotecan plus 5-FU/folinic acid (FA) showed that the latter regimen achieved a higher RR (34% versus 28%) and significantly longer median survival (10.7 versus 6.9 months). Hematological toxicity was lower with the irinotecan/5-FU/FA combination. This regimen has therefore been taken forward into a randomized phase III comparison against a 5-FU/cisplatin doublet. Use of irinotecan-based combinations should also be investigated as an adjuvant treatment (probably in combination with radiotherapy) and in the neoadjuvant setting.