Oral inhalation offers the opportunity of targeting drugs locally to different regions of the respiratory tract or alternatively, using the high surface area of the alveoli for systemic delivery. Pulmozyme and the inhaled insulins (i.e. Exubera and Afrezza) are examples of the scope of pulmonary drug delivery of biopharmaceuticals — albeit with strikingly different commercial success. Particularly, the failure of Exubera and the subsequent overreactions (e.g. the unsubstantiated lung cancer fear), lastingly stunned the field of systemically inhaled protein and peptide drugs. Building on the lessons learned from these early products, a new wave of inhaled biomolecules has recently entered clinical trials. Moreover, oral inhalation has become an attractive alternative for the delivery of small molecules with difficult oral pharmacokinetics and/or extensive liver first-pass metabolism. Advances in inhaler design and our increased understanding of lung physiology continue to make oral inhalation of complex drugs an attractive therapeutic option.