SLE is a serious, debilitating autoimmune disease that affects various organs and body systems. Of all the heterogeneous autoimmune diseases, SLE is perhaps the most heterogeneous. Patients with SLE, who are primarily female, have diverse disease manifestations and severity. SLE is characterised by substantial concentrations of autoantibodies against nuclear antigens, which are thought to be caused by immune cell dysregulation. Until recently, several immunosuppressant agents were used to treat this disease. Efforts to develop drugs against targets potentially involved in disease mechanisms have resulted in the identification and use of BAFF (B-cell activating factor)/APRIL (a proliferation-inducing ligand) inhibitors to treat SLE. Drugs in late-stage development that focus on pathways that are dysregulated in SLE include those that target the interferon pathway, T-cell signalling and B-cell signalling. New therapeutic agents are still necessary because of the unmet medical needs associated with this disease, including insufficient disease control, poor health-related quality of life, comorbidities, toxicity of the majority of therapies and diminished survival. Despite the substantial long-term investment of research, clinical activity and resources for identifying new treatments for this disease, only one new therapy, the biological belimumab, has been approved in the past 50 years. Efforts to develop drugs to address these needs are challenged by problems associated with disease heterogeneity, variable disease mechanisms and trial design. This review provides an overview of current and future treatments, discusses challenges in the SLE drug development process and offers recommendations for overcoming these challenges.