Refinements in our understanding of the pathogenic mechanisms of Type 1 diabetes from studies of animal models and clinical observation have led to new clinical trials to prevent disease progression and restore the loss of beta-cells that defines the disease. Antigen-specific agents have shown initial promise and non-antigen-specific agents now have improved safety compared with older agents. In addition, preclinical studies with other agents have shown efficacy. Ultimately, a combination of immunologic and cellular therapies may be needed to restore metabolic control. Agents that augment recovery of dysfunctional beta-cells, and other compounds that may be able to induce beta-cell replication, are logical additions once immune tolerance is achieved.