Systemic lupus erythematosus is more than a heterogeneous autoimmune disease. It is in fact a syndrome of many different clinical genotypes and phenotypes. This review covers the most recently studied monoclonal antibodies and those currently being investigated. The key trials are summarized, including those for biologics on the market for two decades and those just approved for lupus less than two years ago. The focus will be on the following four: Rituximab, Abatacept, Belimumab, and Epratuzumab. It is a challenge to design the perfect trial and study patients with this disease as each has his or her own unique manifestations, biological markers, and underlying genetic background. However, as our understanding of the immune mechanisms involved in lupus increases; novel therapies will emerge that can be utilized for appropriately selected patients.