Replacement insulin therapy has been the mainstay of type 1 diabetes mellitus (T1D) treatment ever since its introduction into clinical care more than 100 years ago. Despite advances in delivery methods, insulin remains a challenging medication. It is, therefore, not surprising that most people with T1D do not achieve optimal glycemic control and remain at risk of complications. The recent introduction of teplizumab as the first immunotherapy for T1D has ushered in an exciting era where the focus is shifted from metabolic replacement therapy with insulin to proactive disease-modifying treatments that prevent the loss of insulin secretory capacity. At least nine other clinical immunologic interventions have shown phase 2 trial efficacy in preserving β-cell function in T1D. To translate these findings to patient benefit, many changes are required. These include improvements in end points and trial design to accelerate drug development, changing the attitude of healthcare professionals toward novel strategies, and the development of effective screening programs to identify affected individuals in early-stage disease. This will enable a broad portfolio of β-cell preserving therapies to be approved, in turn allowing appropriate selection of immunomodulators tailored to an individual's response with an ultimate goal of "insulin-free T1D."