SUMMARY Monoclonal antibodies (mAbs) have changed the natural course of chronic lymphocytic leukemia (CLL). The most important clinical value in the patients with CLL have at present two mAbs – rituximab and alemtuzumab. The first one is a human mouse antibody, rituximab (IDEC C2B8, Rituxan, Mabthera) that targets CD20 antigen. The second is alemtuzumab (Campath-1H), a humanized form of a rat antibody active against CD52. Over the last few years, several new monoclonal antibodies have been investigated in preclinical studies and clinical trials for patients affected by CLL. The most promising are mAbs directed against CD20, CD22, CD23, CD37 and CD40. New generations of anti-CD20 mAbs were engineered to have augmented antitumor activity by increasing complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity and increased Fc binding affinity. New mAbs directed against CD20 include human mAb ofatumumab (Arzerra, HuMax CD20) and obinutuzumab (GA-101), a novel third – generation fully humanized and optimized mAb. These agents are highly cytotoxic against B-cell lymphoid cells and are evaluated in CLL. Some other new mAbs are also active in indolent NHL. These treatments include epratuzumab, apolizumab, galiximab, anti-TRAIL receptors mAbs, anti-CD37 and anti-CD40 mAbs. Small modular immunopharmaceuticals (SMIP) that retain Fc mediated effector functions have been also developed and investigated in preclinical studies and clinical trials. The SMIP molecules include TRU-015 (anti-CD20) and TRU-016 (anti-CD37). Further studies are needed to elucidate the role of these agents in CLL.