The development of new agents to manage lupus erythematosus has lagged behind other autoimmune rheumatic diseases. This is in large part because lupus is a heterogeneous disorder affecting nine principal domains (organ systems) that are difficult to measure and quantify and can be at variance with each other. Over the last two decades, a variety of guidelines, definitions, candidate surrogate or biomarkers, metrics and composite indices have been presented as benchmarks that can be utilized to assess lupus in clinical trials. Despite this, over 20 agents have failed to achieve their primary outcome measure, some of which are generally believed to be clinically effective. This article presents constructive suggestions and improved strategies in trial design that will hopefully lead to the introduction of new agents for the disease.