Primary gastric non-Hodgkin's lymphomas (PG-NHL) are the most common extranodal lymphomas, representing between 47% and 74% of all gastrointestinal lymphoma cases. In Western countries two histological types, diffuse large B-cell (DLBC) NHL and mucosa-associated lymphoid tissue (MALT) NHL, are more frequently represented, accounting for the majority of gastric tumors after adenocarcinoma. For several years treatment of these PG lymphomas consisted of surgery, chemotherapy and radiotherapy, alone or in combination. In the last two decades however, advances in our understanding of their pathogenesis and biology have changed the treatment strategy, at least as regards the early stages of disease. In addition to making tumor regression possible through the eradication of Helicobacter pylori, which is considered the main pathogenic agent, this understanding has also provided a solid rationale to assess the efficacy of targeted therapy, namely of drugs which interfere with specific molecules expressed by tumor cells or are involved in key growth pathways of these lymphomas. In particular, rituximab, a monoclonal anti-CD20 antibody, radioimmunotherapy, the first-generation proteasome inhibitor bortezomib and lenalidomide have been evaluated. Despite significant antitumor activity in this subset of NHL and manageable toxicity, many questions still remain however about the optimal dose, the best administration schedule and their combination with conventional chemotherapy. This review focuses on the pathogenesis of PG-MALT and DLBC lymphomas, and discusses the results of clinical trials on the impact of new agents on prognosis and survival in these patients, considering also potential new therapautic targets.