In the setting of metastatic or inoperable gastric cancer, the current evidence shows that chemotherapy improves survival in comparison to best supportive care and that combination chemotherapy is superior to monotherapy in terms of survival, response rate and symptom control. Many randomized phase III trials tested different combinations of therapies showing better outcome for cisplatin-containing schedules. In recent years, new drugs, such as docetaxel, oxaliplatin, irinotecan, capecitabine and S1 have also been tested in phase III studies. Unfortunately, in all of these studies, but one, the median survival remained below one year. Although there are no internationally accepted standard regimens, in Europe, ECF (epirubicin, cisplatin, fluorouracil) has been considered the reference regimen; in the US cisplatin-fluoropyrimidine combinations are mainly used, while in Japan, cisplatin with S1 has become the standard. Currently, various targeted agents are being tested in clinical trials and promising data have been recently published for trastuzumab-containing therapy, with median survival exceeding one year. As regards progressive disease, about 20%-50% of patients receive second line chemotherapy and, although two phase III studies reported survival benefit with single-agent chemotherapy, the role of chemotherapy in this setting still needs to be defined. Despite the progress of recent decades, metastatic gastric cancer remains an incurable disease, and treatment options should primarily take into account the quality of life and quality-adjusted survival of patients. The hope for the future is that tailored interventions based on new cytotoxic drugs, targeted therapies and integration of molecular determinants may help to improve the current treatments.