B-cell depletion with unconjugated CD20 monoclonal antibody (mAb) is used to treat rheumatoid arthritis and other autoimmune diseases. CD20-targeted immunotherapy depletes mature B cells through monocyte-mediated antibody-dependent cellular cytotoxicity, but does not effectively deplete pre-B or immature B cells, certain peripheral B cell subpopulations, most antibody-producing cells, or their malignant counterparts. As immature B cells expressing autoreactive antigen receptors are not depleted by anti-CD20 mAb, a new strategy for eliminating autoantigen-selected B cells and for treating early lymphoblastic leukemias and/or lymphomas was developed using CD19-specific mAbs that induce Fcγ receptor-dependent and monocyte-dependent B-cell depletion. Preclinical studies using transgenic mice expressing human CD19 have shown that pre-B cells and their malignant counterparts, as well as pre-existing antibody-producing and autoantibody-producing cells, are depleted. Therefore, CD19-directed immunotherapy is expected to treat diverse pre-B-cell-related and plasmablast-related malignancies, and humoral transplant rejection. Moreover, in contrast to CD20-directed immunotherapies, CD19 mAbs could purge the B cell repertoire of autoreactive clones and reset the developmental clock to a point that curtails the extent of emerging self-reactivity, in addition to reducing autoreactive T-cell activation through the elimination of mature B cells. Humanized CD19 mAbs are expected to enter clinical trials in 2009, offering a new approach for the treatment of autoimmune disease that removes both immature B cells and antibodies with autoreactive specificities. CD19-directed immunotherapy could, therefore, offer a new horizon in B-cell depletion for the treatment of multiple autoimmune diseases.