Significant advances have been made in the last 50 years in developing safe and efficacious aerosol formulations for pulmonary delivery. The key to future innovation may lie at the interface between biology and particle engineering. Improved understanding of biological processes including particle clearance, cellular targeting, intracellular trafficking, and drug absorption are needed to better design formulations that deliver to the "target" with the optimal balance of pharmacodynamic, pharmacokinetic, and safety profiles. More specifically, continued advances are needed in the development of: (1) controlled release formulations; (2) formulations with improved regional targeting within the lungs (e.g., airway versus alveoli and vice versa); (3) formulations containing active targeting moieties; (4) formulation strategies for improving the systemic bioavailability of inhaled macromolecules; (5) formulation strategies for delivering macromolecules, including siRNA and DNA into cells; and (f) formulations with improved dose consistency. It is likely that such innovation will require the development of novel excipients and particle engineering strategies. Future innovation must also take into the account the changing marketplace and the diverse set of customers (patient, healthcare professional, heath authorities, payers, and politicians) who must be satisfied. The pharmacoeconomics of new delivery systems will be closely scrutinized, so it is imperative that cost factors be taken into account. Otherwise, the new technology option may overshoot the evolving inhalation marketplace.