Inhalation development of biomolecules is typically beset with challenges, as evidenced by the lengthy development of inhaled insulin, and often will not be the first choice as a route of administration. To be successful, the eventual product should be well-differentiated from alternative approaches to therapy and there should be a compelling business case for development. The cost of goods of most biologics is high and can present a significant barrier to early development. Preclinical toxicology drug-substance requirements often exceed mid-stage clinical demand, thus requiring significant early, at-risk investments. Despite the challenges, the inhaled route remains a viable choice for all lung conditions and for selected systemic conditions. This is supported by the availability of highly efficient delivery systems and the fact that the majority of lung diseases are either not well managed with current therapies or have no effective treatment at all. Inhaled vaccines are credible prophylactic options for lung-specific or systemic conditions, while strong cases can be made for the use of select peptides and proteins for systemic disease where a therapeutic advantage can be argued. Although there are few novel clinical-stage biologics currently under development, considerable feasibility and preclinical work is ongoing based on patent and literature activity. What the next ‘success’ will be is hard to predict but after factoring in attrition rate, logic dictates that many inhaled biotherapeutics will eventually be in clinical use.