The identification and study of autoimmune dis-eases has taught us that recognition of self-antigens can have devastating consequences. Yet there is a paradox to autoreactivity: when correctly balanced, it is at the heart of robust self-tolerance. This concept gives rise to several questions. Can this balance be manipulated? And if so, by what means and through which mechanisms? What are the rules that govern this opportunity to restore homeostasis? Studies in a variety of animal models, which act as replicas of the major chronic inflammatory diseases that affect humans, have offered many answers to these questions. One of the clearer outcomes is that delivery of autoantigens, administered at different disease stages via a variety of routes, can provide robust, sustained health and protection from inflammatory autoimmune disease. The most appealing element to this approach, termed antigenspecific immunotherapy (ASI), has been that it not only provides an effective means of controlling the autoimmune response via induction or restoration of-cell–specific tolerance, but that it may achieve these goals without major concerns over safety and certainly without the specter of immune suppression. Yet significant questions remain. Are we doing enough to realize the potential of this sacred cow? How do we move from concept to reality?

In this article, we provide an update on the mechanisms through which ASI is currently thought to operate. We discuss why, despite this body of knowledge, alternative, non-ASI approaches have emerged as the current vogue. We argue that more should be done to counter this trend and realize the potential of ASI, including strategies that combine its strengths with those of other complementary ways forward.