Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is clinically heterogeneous and affects multiple organs. Lupus nephritis is the most frequent severe manifestation of SLE. Conventional immunosuppressive therapy has increased the life expectancy of patients diagnosed with lupus nephritis, but only 70-80% of patients respond to this treatment and its adverse effects are considerable. B cells are central to the pathogenesis of SLE and are, therefore, an attractive therapeutic target. B-cell depletion has been used successfully to treat other autoimmune diseases, such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis, and many case reports and small nonrandomized trials of B-cell-depleting agents in patients with lupus nephritis have reported positive results. By contrast, two large placebo-controlled trials designed to investigate the efficacy of the B-cell-depleting agents rituximab and ocrelizumab as a treatment for lupus nephritis, failed to meet their primary efficacy end points (LUNAR and BELONG, respectively). This Review discusses the current evidence on the use of B-cell depletion in the treatment of lupus nephritis, which is derived from case studies and clinical trials including a total of over 800 patients.