Systemic lupus erythematosus (SLE) is a chronic, occasionally life threatening, multisystem disorder. Patients suffer from a wide group of symptoms and have a variable prognosis that depends of the severity and type of organ involvement. The clinical manifestations include fever, skin lesions, arthritis, neurologic, renal, cardiac, and pulmonary disease. The pathogenesis of this serious multisystem autoimmune disease is based on polyclonal B cell immunity, which involves connective tissue and blood vessels. The novel biologic therapies have raised hope for more effective and safer treatment for SLE. Although definitive studies are still under development, the impressive preliminary results of therapies specifically targeting B cells and the signaling pathways involved in B-T-cell interactions suggest that the depletion of memory cells accounts, at least in part, for the clinical efficacy of rituximab therapy in patients whose disease is resistant to other immunosuppressive therapies. However these findings, although provocative, require further investigation in larger cohorts.