Approximately 215,000 people younger than 20 yr of age, or 1 in 500 children and adolescents, had diabetes in the United States in 2010--and the incidence is rising. We still have insufficient knowledge about the precise mechanisms leading to the autoimmune mediated β-cell destruction in Type 1 diabetes, and the β-cell failure associated with insulin resistance in Type 2 diabetes. Long-term complications are similar: micro- and macrovascular disease occurs prematurely and presents an enormous burden on affected individuals, often as early as in middle age. In Type 1 diabetes, technological advances have clearly improved blood glucose management, but chronic peripheral over-insulinization remains a problem even with the most advanced systems. Thus, in Type 1 diabetes our research must focus on 1) finding the stimulus that ignites the immune response and 2) developing treatments that avoid hyperinsulinemia. In Type 2 diabetes in youth, the challenges start much earlier: most young patients do not even benefit from existing therapies due to non-compliance. Therefore, prevention of Type 2 diabetes and improvement of compliance, especially with non-pharmacological interventions, are the greatest challenges.