Although B cells represent major contributors to rheumatoid arthritis (RA) pathogenesis, their precise roles in the induction and maintenance of abnormal immune activation in this entity remains poorly understood. As proof of principle, rituximab, a chimeric B cell depleting anti-CD20-antibody, has demonstrated that depletion of B cells can substantially improve signs and symptoms as well as physical function and inhibit radiologic progression that led to the approval of this agent to treat patients with moderate to severe RA lacking response to TNF-alpha blocking agents in 2006. Placebo-controlled clinical trials as well as subsequent studies and experiences further contributed to our understanding of the mechanism of action of rituximab, but a number of open questions remain. This review summarizes some lessons learned from B cell depletion in RA including particular safety aspects. Of importance using this therapy is that it apparently provides the highest likelihood of response in seropositive RA patients. This observation differentiates it from other currently available therapies and closes the conceptual loop that the underlying immunopathogenesis involves B cells requiring 'targeted' therapy.