Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease resulting in the destruction of the insulin-secreting β cells. Currently, there is no established clinical approach to effectively suppress long-term the diabetogenic response. Genetic-based vaccination offers a general strategy to reestablish β-cell specific tolerance within the T-cell compartment. The transfer of genes encoding β-cell autoantigens, anti-inflammatory cytokines and/or immunomodulatory proteins has proven to be effective at preventing and suppressing the diabetogenic response in animal models of T1D. The current review will discuss genetic approaches to prevent and treat T1D with an emphasis on plasmid DNA- and adeno-associated virus-based vaccines.