Systemic lupus erythematosus (SLE) is a complex autoimmune disease with substantial clinical heterogeneity. Current treatments for SLE are effective at reducing morbidity and mortality but fail to provide a cure, and they frequently have adverse effects. Traditional treatments include NSAIDs and antimalarial agents, which are the first-line therapies for mild SLE. In addition, glucocorticoids and cytotoxic or immunosuppressive agents—such as azathioprine, mycophenolate mofetil, cyclophosphamide, cyclosporine and methotrexate —are used for SLE with organ involvement. Advances in understanding the immunopathogenesis of SLE have led to the development of targeted immunotherapies, such as the anti-BAFF antibody belimumab, which has been approved as an add-on therapy for patients who have active disease despite receiving standard therapy. This Review presents an overview of the current therapies and nonpharmacological management approaches for SLE, and discusses the best approaches for treating specific disease manifestations such as lupus nephritis, neuropsychiatric lupus and cutaneous lupus erythematosus.