Nephritis is the most frequent severe manifestation of anti-neutrophil cytoplasm antibody associated (ANCA) systemic vasculitis (AASV) and systemic lupus erythematosus (SLE) and carries substantial morbidity. Although immunosuppressive medications and glucocorticoids are effective at inducing remission, patients still suffer from high relapse rates and experience significant treatment-related toxicity. Rituximab (RTX), a chimeric antibody directed against CD20, found on B lymphocytes, shows potential as a treatment for both AASV and SLE. Although direct comparisons with standard therapies are currently unavailable, patients in several studies of refractory and relapsing disease have achieved a remission despite the failure of standard therapies. These reports are supported by several lines of experimental evidence that underlie the rationale for using targeted B-cell therapies and have improved our understanding of the pathogenesis of these complex diseases. Future randomized control trials and long-term follow-up studies are required to confirm the role of RTX and other B-cell targeting therapies in AASV and SLE.