Type 1 diabetes mellitus is a chronic disease characterized by autoimmune destruction of insulin-producing beta-cells. Current insulin replacement therapies offer many patient benefits, but do not prevent secondary complications when glycemic control is insufficient and are associated with the risk of hypoglycemia. Therefore, more efficient and safer therapies are still required. Gene therapy is considered a new approach/tool to treat diabetes. Important advances in the field of gene therapy have made vectors both more efficient and safer in delivering genes to most tissues and cell types. In this review, we first analyze the key issues that should be considered for designing a new gene therapy approach for diabetes and second, we discuss main approaches currently under investigation for this disease. Finally, most relevant results in the field are presented.