With the approval by the FDA in 2011 of a biologic agent (namely belimumab) for the treatment of systemic lupus erythematosus (SLE), optimism abounds that additional biologic (and nonbiologic) agents will be similarly endorsed. Given the numerous immune-based abnormalities associated with SLE, the potential therapeutic targets for biologic agents and the candidate biologic approaches are also numerous. These approaches include: biologic agents that promote B-cell depletion, B-cell inactivation, or the generation of regulatory B cells; biologic agents that induce T-cell tolerance, block T-cell activation and differentiation, or alter T-cell trafficking; biologic agents that target the B-cell activating factor (BAFF) axis, type I interferons, IL-6 and its receptor, or TNF; and the adoptive transfer of ex vivo-generated regulatory T cells. Owing to the great heterogeneity inherent to SLE, no single approach should be expected to be effective in all patients. As our understanding of the pathogenic mechanisms of SLE continues to expand, additional therapeutic targets and approaches will undoubtedly be identified and should be fully exploited.