A mathematical model was developed for predicting drug residence kinetics in various regions of the human respiratory tract (RT). The model allows for regional deposition of different dose fractions (following mouth inhalation of various particle sizes according to four popular breathing regimes). Predicted alveolar deposition was dependent on the mode of inhalation and breath-holding. Deposition in the ciliated airways, however, was largely unaffected by breath-holding and was at a maximum for aerodynamic diameters between 5-9 micron (slow inhalation) and 3-6 microns (fast inhalation). Selected mucociliary and absorption rate constants determined the durations (T) taken to deplete the initial deposition in a chosen lung region to a selected minimum dose fraction (MDF). Values of T for an MDF of 0.01 in the ciliated airways were dependent on aerosol size, mode of inhalation, and rate of dissolution. In the case of rapidly dissolving solutes, the maximum duration was short (1-2 h) and occurred at particle sizes and modes of inhalation which maximized deposition in the conducting airways. For less soluble particles, however, T in the same airways could approach 12 h due to a prolonged supply of particles from the alveolar regions. The optimal size distribution and the mode of inhalation for maximum duration differed substantially in each case. The model enables formulation of testable hypotheses relating to the extension of local drug residence in the RT following inhalation of therapeutic aerosols.