Successful clinical efficacy trials have been recently completed for a growing array of new biologics. Prospects are improving for rational therapeutic interventions that potently interrupt adaptive immune response pathways. By contrast, disappointing results with antigen-based therapeutics highlight the difficulties of achieving tolerance in the context of active autoimmunity. Combination immunotherapy is probably necessary to sequentially or simultaneously inhibit inflammation, uncouple innate immune pathways, interrupt or ablate the adaptive memory response and promote antigen-specific tolerance in a suitable immunological context.