Gastric cancer is most chemosensitive among gastrointestinal tumors. However, the role of chemotherapy in advanced disease and its advantage over best supportive care has been adequately addressed only in the last decade. First generation regimens, such as 5-Fluorouracil (5-FU), Doxorubicin, Mitomycin C (FAM) have been used until early 90's, when evidence from randomized studies came up in favour of second generation regimens, such as 5-FU, Doxorubicin, high-dose Methotrexate (FAMTX), which in turn was proven less active than a third generation regimen, such as epirubicin, cisplatin, continuous infusion 5-FU (ECF) in a randomized study. Newer treatment options came up over last years. The Swiss Group for Clinical Cancer Research has carried out a randomized three-arm phase II study with ECF or docetaxel, cisplatin (TC), or docetaxel, cisplatin, 5-FU (TCF) in advanced gastric cancer. TCF has been selected as the combination to be further evaluated in a formal comparison with ECF. Oxaliplatin is being tested in advanced gastric cancer. Two recently published phase II studies of biweekly infusional 5-FU, folinic acid, and oxaliplatin have shown a considerable therapeutic activity. Irinotecan is another drug under investigation in advanced gastric cancer, both as single agent and in combination. A randomized phase II-III study of irinotecan plus cisplatin or irinotecan plus folinic acid/5-FU has recently been completed; the latter arm was proven worth undergoing a formal comparison with a standard CF regimen. Oral fluoropyrimidines represent a suitable therapeutic option in selected groups of patients. Marimastat is a matrix metalloproteinase inhibitor, whose main toxicity is musculoskeletal. A randomized phase III study of marimastat versus placebo as maintenance therapy in advanced gastric cancer has shown a significant survival advantage for the marimastat arm, both in the total patient population and in the subgroup of patients who had previously received chemotherapy. Since a clear gold standard for advanced gastric cancer does not yet exist, the inclusion of patients in well designed clinical trials is to be considered the best treatment option.