Gastric cancer continues to be one of the most prevalent malignancies. It is estimated that it is the fifth most frequent malignancy, and is considered the third mortality cause worldwide due largely to the fact that more than 70% of the cases are detected in advanced stages where, although first-line therapy has shown benefits in terms of survival, many of these patients showed disease progression, which raises the challenge of optimizing subsequent lines of therapy and developing new and better therapeutic options. The role of second-line therapy has been widely discussed due to the fact that although there is evidence regarding the benefits of some drugs such as docetaxel, paclitaxel, and irinotecan in second-line therapy, and that this benefit has shown a reduction of approximately 18% in the risk of death, there is still a concern regarding the toxicity profile, and an adequate choice of the best drugs as regards efficacy, toxicity, and patient characteristics continues to be a topic of discussion. The following review explores the most recent data published about the role of chemotherapy as second line therapy, as well as the clinical trials performed with target therapies showing promising results, which will allow for the improvement of gastric cancer treatment.