Gastric cancer is one of the most common cancers and the second leading cause of cancer-related death. So far, the only curative treatment for gastric cancer is surgery. However, approximately half of all patients present with nonoperable tumors. Therefore, combination chemotherapy regimens are being accepted nowadays as first-line treatment for this disease. Despite the numerous efforts of randomized trials on advanced gastric cancer, no globally accepted regimen has yet been established. Historically, the most widely adopted protocols use 5-fluorouracil or platinum-based therapy with a response rate not exceeding 50% in combination therapy with a high rate of toxicity. Recently, many new drugs have emerged on the market and have been used in treating advanced or metastatic gastric cancer allowing the creation of new combination regimens with better clinical benefit. The combination of irinotecan plus capecitabine is one of these new combinations that seem to provide an acceptable response rate and good toxicity profile. In this article, we review the efficacy, tolerability, and feasibility of this combination for the treatment of advanced or metastatic gastric cancer and we summarize the clinical trials using this regimen.