Background: Therapeutic engineering of insulin analogs is ordinarily limited by a trade-off between pharmacokinetics and stability. Results: Substitution of Tyr B26 in a rapid-acting insulin analog by 3-iodo-Tyr B26 enhances its biophysical and pharmaceutical properties. Conclusion: An unnatural amino acid substitution circumvents insulin pharmacokinetic/stability trade-off. Significance: Nonstandard mutagenesis can optimize the molecular properties of therapeutic proteins.