Identification of the pancreas as the site of the defect in diabetes mellitus by von Mehring and Minkowski in 1889 led eventually to the identification and successful extraction of insulin in 1921 by Banting and Best. The availability of insulin for therapy shortly afterwards dramatically changed the lives of patients with diabetes who previously had a life expectancy of less than 2 years. In the 80 years since, major benefits have accrued. In the year 2000 alone, it is estimated that about 4.8 million years of life were gained for patients with type 1 diabetes as a result of insulin treatment, assuming a life expectancy of 1.5 years in its absence and a global prevalence of 5.1 million. Since insulin was first introduced into clinical practice there have been major developments in its production, purification, pharmaceutical formulation, and methods of delivery. However, despite these advances, microvascular and premature macrovascular complications persist as the main cause of morbidity and mortality in both type 1 and type 2 diabetes and represent a constant reminder that current therapeutic and management strategies, for the vast majority of our patients, remain woefully inadequate. In this chapter, we describe the many attempts made to develop alternative, less invasive routes for the delivery of insulin while focusing on recent progress achieved with inhaled insulins, which may provide the first opportunity for at least partial independence from subcutaneous injections.