In type 1 diabetes (T1D), pancreatic beta-cells are attacked and destroyed by the immune system, which leads to a loss of endogenous insulin secretion. The desirable outcome of therapeutic intervention in autoimmune diseases is the restoration of immune tolerance to prevent organ damage. Past trials with immune suppressive drugs highlight the fact that T1D is in principle a curable condition. However, the barrier in T1D therapy in terms of drug safety is set particularly high because of the predominantly young population and the good prognosis associated with modern exogenous insulin therapy. Thus, there is a general consensus that chronic immune suppression is associated with unacceptable longterm safety risks. On the other hand, immune-modulatory biologicals have recently failed to confer significant protection in phase 3 clinical trials. However, the concept of antigen- specific tolerization may offer a unique strategy to safely induce long-term protection against T1D. In this review, we analyze the potential reasons for the failure of the different tolerization therapies, and describe how the concept of antigen- specific toleraization may overcome the obstacles associated with clinical therapy in T1D.