The advancement in protein engineering offers targeted development of insulin analogs that display either faster absorption kinetics or longer time-action profiles compared with human insulin and, therefore, more closely mimic endogenous insulin secretion. Insulin glulisine (3(B)Lys29(B) Glu-human insulin) is a new fast-acting analog that provides absorption and onset of action more rapidly with a shorter duration of action compared with regular human insulin, and thus better resembles physiologic mealtime insulin requirements. Insulin glulisine has been designed to exhibit intrinsic stability while maintaining rapid deployment of insulin monomers. Pharmacokinetic and pharmacodynamic profiling of insulin glulisine in healthy subjects and patients with type 1 and type 2 diabetes not only confirms the rapid absorption and fast action of insulin glulisine compared with human insulin, but also provides evidence that the unique drug formulation may offer additional benefits. Insulin glulisine complements insulin glargine (21(A)-Gly30(Ba)-L-Arg-30(Bb)-L-Arg-human insulin), the first long-acting basal insulin analog that displays a smoothed time-action profile with a 24-h duration of action. Together these analogs offer patients a more physiologic approach to insulin replacement.