Dendritic cells (DC) play important roles in the initiation of immune responses and in the maintenance of self-tolerance. We have been studying the role of DC in the pathogenesis of type 1 diabetes and exploring the ability of specific DC subsets to prevent diabetes in non-obese diabetic (NOD) mice. DC presenting low doses of antigen are capable of inducing and expanding T-regulatory (Treg) cells that have potent suppressive function. We review here our recent findings in this area and highlight the ability of semi-mature therapeutic DC to induce Treg expansion in the absence of exogenous antigen. We discuss how the presentation of endogenous self-antigen by DC may represent a natural mechanism for peripheral self-tolerance that can be harnessed to prevent autoimmunity.