Indolent non-Hodgkin lymphomas are characterized by a low proliferation, but relapses are frequent. The gold standard treatment at diagnosis is still unknown. Careful watchful waiting is appropriate in asymptomatic patients with low tumor burden. In symptomatic patients that require treatment, chemoimmunotherapy with rituximab in association with chlorambucil, CVP, CHOP, fludarabine-containing regimens or bendamustine is recommended. Maintenance treatment with rituximab after induction is effective and safe and determines an improvement of progression-free survival respect observation; also, radioimmunotherapy consolidation is effective. High-dose chemotherapy with autologous stem cell transplantation is useful in relapsed/refractory patients. Knowledge on biology and pathogenesis of lymphoma represents the basis for the introduction of targeted therapy. New drugs such as bortezomib, lenalidomide, humanized monoclonal antibody anti-CD20 or anti-CD22 are tested in relapse and front-line patterns, with encouraging results. These therapeutic approaches improved the outcome of indolent lymphoma's patients and may represent a paradigm for the treatment of Waldenström's macroglobulinemia.