A mathematical model of aerosol deposition has been developed for drug delivery protocols and used successfully to simulate inhalation exposure tests with human subjects. Therefore, we have used the validated model to address the delivery of inhaled pharmaceuticals as a function of disease-induced changes in airway structure. Clinical data from the literature had suggested that progressive lung disease associated with cystic fibrosis (CF) could compromise the successful administration of pharmacologic drugs used in its treatment, hence it was studied. We described the lungs of patients inflicted with CF by different morphologies (representing the processes of airway obstruction, infection and inflammation) than healthy (control) subjects. Affected ventilatory parameters were also examined to demonstrate their effects upon drug disposition. Particle distributions were computed on a generation-by-generation basis. Deposition patterns were dramatically affected by CF-produced alterations in dimensions. The reduced airway caliber in CF enhanced the total dose delivered to the tracheobronchial compartment by 200-300% relative to controls. The spatial distributions of aerosols were completely different in CF patients, being selectively deposited within congested airways. In medical practice the model can be tailored to any specific airway disease. Regarding targeted delivery, the results have relevance to (1) site-specific acting pharmaceuticals in tracheobronchial airways and (2) drugs designed for systemic delivery via deposition in alveolated airways.