B cell depletion with rituximab, a chimeric monoclonal antibody that selectively targets B cells by binding CD20, has been used off label in severe and resistant systemic lupus erythematosus (SLE) for over two decades. Several biological mechanisms limit the efficacy of rituximab, including immunological reactions towards the chimeric molecule, increased numbers of residual B cells, including plasmablasts and plasma cells, and a post-treatment surge in B cell-activating factor (BAFF) levels. Consequently, rituximab induces remission in only a proportion of patients, and safety issues limit its use. However, the use of rituximab has established the value of B cell depletion strategies in SLE and has guided the development of several improved B cell depletion therapies for SLE. These include enhanced monoclonal antibodies, modalities that redirect the specificity of patient T cells using chimeric antigen receptor T cells or bispecific T cell engagers, and combination treatment that simultaneously inhibits the BAFF pathway. In this Review, we consider evidence gathered from over two decades of using rituximab in SLE and examine how B cell depletion therapies could be further optimized to achieve immunological and clinical efficacy. In addition, we discuss the prospects of B cell depletion strategies for personalized treatment in SLE based on genetic research and studies in pre-symptomatic individuals.