In contrast to other interfaces between the outer and inner environment, such as the skin and gastrointestinal tract, the lungs are ideally suited for the delivery of polypeptides and proteins to the systemic circulation. There is a wealth of experience from aerosol physics and lung biology to support the idea that insulin delivery via the lungs is an effective strategy. The elaborate branching network of airways, the extensive surface area of the deep lung, and the thin air-blood barrier make it possible to deliver insulin and other proteins to the parenchyma, where it can be absorbed into the pulmonary circulation and become available throughout the body. Protein-containing aerosols in inspired air deposit throughout the respiratory tract because of the following forces: gravity, diffusion, and inertial impaction. Lung anatomy, breathing pattern, and particle size determine the influence of these forces. Once deposited in the lungs, most protein-containing formulations quickly dissolve in airway or alveolar lining fluid. Then, a significant fraction of insulin is transported across the air-blood barrier into the blood, where it continues to be biologically active. A substantial fraction--usually the majority--is cleared from the lungs or degraded within the lungs.