Immune tolerance is necessary to prevent the immune system from reacting against self, and thus to avoid the development of autoimmune diseases. In this review, we discuss key findings that position dendritic cells (DCs) as critical modulators of both thymic and peripheral immune tolerance. Although DCs are important for inducing both immunity and tolerance, increased autoimmunity associated with decreased DCs suggests their nonredundant role in tolerance induction. DC-mediated T cell immune tolerance is an active process that is influenced by genetic variants, environmental signals, as well as the nature of the specific DC subset presenting Ag to T cells. Answering the many open questions with regard to the role of DCs in immune tolerance could lead to the development of novel therapies for the prevention of autoimmune diseases.