The discovery of insulin in 1922 marked the beginning of research and development to improve the means of delivering protein therapeutics to patients. From that period forward, investigators have contemplated every possible route of delivery. Their research efforts have followed two basic pathways: one path has focused on non-invasive means of delivering proteins to the body; and the second path has been primarily aimed at increasing the biological half-life of the therapeutic molecules. Thus far, the commercial successes of protein delivery by the nasal, oral and pulmonary routes have been more opportunistic rather than the application of platform technologies applicable to every protein or peptide. In several limited cases, sustained delivery of peptides and proteins has employed the use of polymeric carriers. More successes have been achieved by chemical modification using amino acid substitutions, protein pegylation or glycosylation to improve the pharmacodynamic properties of certain macromolecules. Today, commercial successes for protein and peptide delivery systems remain limited. The needle and syringe remain the primary means of protein delivery. Major hurdles remain in order to overcome the combined natural barriers of drug permeability, drug stability, pharmacokinetics and pharmacodynamics of protein therapeutics.