The emergence of new targeted therapies is rapidly improving the treatment of autoimmune disease. These drugs have been variably designed to deplete specific T and B cell subsets, interrupt receptor-ligand interactions, and inhibit the activity of inflammatory mediators relevant to immune function. Abatacept, a co-stimulatory blocker, and rituximab, a B cell depleting antibody, are among the approved therapies seeking new indications, while the newer therapies include Fc receptor-non-binding CD3-specific antibodies, IL-12/23 antibodies, an IL-6 receptor antagonist, a sphingosine-1-phosphate agonist, and small molecule inhibitors of intracellular protein kinases. Antigen-specific therapies are in their infancy, but the latest results administering glutamic acid dehydrogenase peptide to type 1 diabetics are promising. In the future, treatment strategies may increasingly explore the use of drug combinations acting at multiple sites of aberrant immunoregulation to achieve disease quiescence and immune tolerance.