Non-Hodgkin’s lymphoma (NHL) is a heterogeneous group of B- and T-cell cancers, with a large variety of patterns of growth, clinical presentations, and responses to treatment. Chronic lymphocytic leukemia (CLL) is a B-cell chronic proliferation not very different from the small lymphocytic lymphoma, and both diseases are often treated identically (1). The outcome depends on histological subtype, tumor characteristics, host responses, and treatment. About 90% of lymphomas have a B-cell phenotype, and for them recent therapeutic progress came from the introduction of monoclonal antibodies (mAb) alone or in combination with chemotherapy (2–4). The first antigen that has been targeted for therapeutic purpose with success was the CD20 antigen, a trans-membrane protein expressed by more than 99% of B-cell lymphomas. Rituximab was the first mAb engineered to target the CD20 antigen and first approved mAb for the treatment of lymphoma patients. Through the last 10 years, clinical trials with rituximab have confirmed its efficacy in follicular lymphoma (FL) as well as in aggressive lymphomas and its use has expanded significantly beyond the initial indication of indolent B-cell lymphomas to virtually any CD20-positive 126lymphoma. The addition of rituximab to chemotherapy was the first real progress in 10 years that has significantly prolonged the survival of patients with B-cell lymphomas (4,5). In recent years, several other mAb targeting CD20 or other lymphocyte antigens appeared, some of them associated with a toxin or a radioisotope. However, most of the data generated today on mechanisms of action or clinical efficacy have been for rituximab. Thus, rituximab will serve as example in this review, and differences with other mAb will be outlined when necessary.