Induction of antigen-specific tolerance is a promising therapeutic approach for autoimmune diseases. Despite many successes in animal models, translation to the clinic has been hampered by lack of efficacy, disease exacerbation and hypersensitivity reactions. Novel approaches aim at inducing tolerance to several immunodominant antigens at the same time. Besides several key issues like the route of administration, dose of antigen and nature of antigen, antigen-specific therapies should be performed early in the disease course in order to block the diversification of autoreactive specificities and thereby prevent disease progression. It is essential that clinical trials are accompanied by appropriate immunologic analyses to be used either as a parameter to monitor safety and efficacy, but also to get a better understanding of the mechanisms of disease and the respective treatment approach. Here we will discuss the mechanisms of tolerance, the experience with trials in MS and present novel approaches.