Treatment development for SLE has been marked by failures of many later phase studies, representing billions of dollars of lost research and development funding. Recently, more successful Phase II trials have tested reductions in background medications, novel stringent endpoints, and identification of informative immunologic subsets to achieve greater treatment effects. A large number of agents with promising novel biologic mechanisms have continued to enter clinical development, and momentum is building to capitalize on newer strategies for trial designs. Widespread SLE drug development is proceeding despite setbacks and controversies. Approaches focusing on patients with high disease activity, reduction of background polypharmacy, or increased endpoint stringency provide strategies that might improve interpretation of trial results. Pharmacodynamics of immune-modulation is a field in its infancy, but ripe for development.