There are multiple immune-based therapeutics available for some of the most prevalent autoimmune diseases, but for others, there are few or no approved immune therapies. This dichotomy poses discrete challenges. First, for diseases in which multiple therapy choices exist, a rational decision tree is required to select the best therapy. Second, we must devise new strategies for the autoimmune diseases that have the highest unmet clinical need. This commentary outlines new strategies for designing more efficient and selective approaches for immune therapy of autoimmune diseases.