Immune modulators, such as interferon beta and glatiramer acetate, have focused on T-cells as the primary therapeutic target, although both drugs affect other cell types as well. There has been a renewed interest in the potential roles of both antibody-dependent and antibody-independent B-cell responses in multiple sclerosis (MS) and its animal model. Accumulating data suggest that the contribution of B-cells and their secreted products to central nervous system (CNS) inflammatory diseases may relate to the abilities of B-cells to (1) differentiate into plasmocytes that produce antibodies, (2) function as antigen-presenting cells, contributing to Tcell activation, (3) produce effector cytokines that may modulate the local immune environment, (4) harbour the Epstein Barr virus in a chronically activated state, and (5) play a role in formation and maintenance of new lymphoid foci within the CNS. Understanding the biological and clinical impact of selective B-cell interventions such as rituximab (Rituxan, Genentech Inc., San Francisco, CA, USA) becomes of particular interest. This review will present the rational for B-cell based therapies in MS and related diseases and preliminary data suggesting a therapeutic benefit in MS and related diseases. In addition, other therapies aiming at CD20 will be reviewed.