CD20 is a particularly appealing target that is expressed on the surface of almost all B cells, with no significant shedding, secretion or internalization. In contrast to the demonstrated efficacy of anti-CD20 strategies in various B-cell lymphoproliferative disorders, the role of such therapy in multiple myeloma is undetermined and controversial. The expression of CD20 by myeloma cells is heterogeneous, and can be detected only in 13-22% of patients. However, there is increasing interest in testing anti-CD20 therapy in myeloma because of recent studies suggesting the existence of clonogenic CD20-positive precursor B cells in the disease. This article reviews the rationale, preclinical and clinical activity of anti-CD20 therapy in myeloma. Clinical trials show that anti-CD20 therapy with rituximab elicits a partial response in approximately 10% of CD20+ patients with multiple myeloma. In addition, there is preliminary evidence of disease stabilization in 50-57% of CD20+ patients for a period of 10-27 months. Further large-scale clinical trials are therefore needed to establish the role of this promising strategy in the treatment of myeloma.