Pulmonary delivery of insulin is more than a promise in the treatment of diabetes mellitus. Inhaled insulin seems at least as efficacious as the conventional regimen of subcutaneous insulin and/or oral glucose-lowering agents in both type 1 and type 2 diabetes mellitus. Improved metabolic control and the use of a non-invasive route of administration represent the main benefits of this new treatment. Several physico-chemical factors could reduce the bioavailability of inhaled insulin. Indeed, both deep-lung deposition and adsorption of insulin variously depend on the type of propellants used, speed of air flow, particle size and velocity, drug deposition into the throat and larger bronchial tree. These factors, in turn, depend on the pulmonary delivery systems used and on respiratory mechanics and flows. Furthermore, the pharmacokinetics of inhaled insulin is affected by smoke, which increases its absorption, and by lung diseases, which decrease the available alveolar-capillary surface. Selected abnormalities of respiratory function complicate both type 1 and type 2 diabetes mellitus and a mild depression of carbon monoxide lung transfer after a 6-month period of treatment with inhaled insulin has been reported. Finally, results from some longitudinal studies suggest that diabetes might speed up the age-related decline of lung volumes and probably alter the pharmacokinetics of inhaled insulin, particularly in the elderly. Clarifying these issues is mandatory in order to define the indications and safety of inhaled insulin.