Over the last three decades, there has been a wide range of options in the management of follicular lymphoma, including observation (watching and waiting), single-agent or combination (e.g., alkylating agents, anthracyclines or purine nucleoside analogs) radiation therapy, immunotherapy alone or in combination with chemotherapy, and interferon. A number of trials studying the treatment of follicular lymphoma patients have investigated the benefit of adding rituximab either concurrently or sequentially to chemotherapy. In the current review, these studies were selected based on the fact that they were randomized Phase III studies with two arms comparing chemotherapy alone with rituximab-based chemo-immunotherapy regimens. In September 2006, the US FDA approved the use of rituximab (Rituxang(R)) as front-line treatment of patients with follicular lymphoma in combination with cyclophosphamide, vincristine and prednisone (R-CVP) as well as for the treatment of patients with low-grade non-Hodgkin's Lymphoma who achieve stable disease or better following first-line treatment with the same chemotherapy regimen (CVP -> R). The European Medicines Agency also approved the use of rituximab (MabThera(R)) as front-line treatment of patients with stage III-IV disease in combination with CVP chemotherapy. In conclusion, although the clinical studies discussed in this article provide evidence for a progression-free survival benefit, overall survival advantage was clearly shown for the first time in a recent update of the initial study in patients with follicular lymphoma.