The clearance of airway secretions is vital in protecting the mammalian lung from pollution and infection. Diverse animal models have been used to study lung diseases associated with impaired secretion clearance. The extrapolation of data from animal models to humans is based on the assumption that there are structural and functional similarities in the airway epithelium and secretions. This manuscript reviews regulation of mucus secretion as well as the physical and transport properties of respiratory mucus. As tracheal size increases, the rigidity of airway secretions decreases, and rigidity is inversely correlated with mucociliary transportability. These differences are placed in the context of previously reported species and regional differences in transepithelial potential difference and the tracheobronchial epithelial cell population. Tracheal mucus transport velocity varies with the species studied and has been shown to positively correlate with tracheal surface area. A progressive increase in the rate of mucus transport from the small to the large airways has also been reported. The reduction in mucus rigidity from small to large airways could be one of the mechanisms responsible for velocity gradients, which facilitate mucociliary transport. Because airway dimensions, rather than anatomic level of the airway, may better predict epithelial secretory response, studies to assess the physiologic responses in human airways require the use of an animal model with a similar-sized airway.