Despite marked decreases in incidence over the last century, particularly in developed countries, gastric cancer is still the second-most common tumor worldwide. Surgery remains the gold standard for the cure of locoregional disease. However, in most countries, the diagnosis is made at an advanced stage, and the 5-year survival for surgically resectable disease stays far below 50%. The efficacy of chemotherapy and/or radiation therapy in addition to surgery has been actively studied over the last 30 years. Unfortunately, with few exceptions, most studies of adjuvant therapy in gastric cancer have given deceiving results. The purpose of this review is to address the reasons for our failure to objectivate an improvement in the cure of gastric cancer with adjuvant treatment in most trials, and to consider potential solutions. The low efficacy of chemotherapy regimens available up to now may have hampered our progress. In addition, many previous studies suffered limitations of design or methodology (e.g. low accrual, inadequate disease stage selection, inadequate surgical treatment) that may have obscured a treatment effect. Furthermore, the reduced treatment tolerance of post-gastrectomy patients, perhaps due to their poor nutritional status, results in decreased or delayed adjuvant systemic therapy, with potential adverse consequences in its efficacy. Among potential solutions, the arrival of new drugs, taxanes and topoisomerase I inhibitors in particular, which have shown encouraging results in metastatic disease, may increase the impact of chemotherapy in a multidisciplinary treatment approach. Pre-treatment with chemotherapy and/or radiation therapy prior to surgery may also be advantageous, averting the problems associated with post-surgical treatment. Such an approach has been shown to be feasible in phase II studies, and is relatively well tolerated by patients. Several carefully designed randomized phase III trials are underway to answer this question.