The objective for diabetes treatment remains the elimination of insulin therapy, and for this to happen, further advances in diagnostics and preventive therapy are needed. Glucose-sensitive cellular delivery of insulin is highly desired but still in its infancy regarding production and implementation. In the meantime, the development of insulin that is responsive to glucose, or at least that is much less variable in its action within and across broad patient subgroups, is crucial. Supplementation of insulin therapy with incretin-based drugs has already demonstrated its value, and further expansion of this pharmacological toolset will probably lead to new and improved treatments. In this regard, tissue- and receptor-selective insulin analogues are of great interest given their potential to restore metabolic homeostasis without excessive insulin action at undesired sites.