Animal models are essential for understanding the fates and effects of inhaled materials, because invasive methods are frequently necessary to provide the desired information. Because of the variability in humans of particle deposition, clearance, and effects, numerous animal models have been used in inhalation studies. Furthermore, humans are not typical mammals in some ways that affect inhalation phenomena. Humans have less fur, longer gestation and life times, simplified nasal structure, and symmetric bronchial branching in relation to other mammals. However, experience, plus the genetic similarity among mammals, underpins the use of animal models. Mammals are varied with respect to their inhaled particle deposition and clearance phenomena. Total inhaled aerosol deposition probability versus particle-size curves are qualitatively similar for various mammals of similar body mass, despite airway anatomy differences. However, more species variation is seen in regional particle deposition curves, complicating aerosol study design. The rates of clearance of deposited slowly dissolving particles are animal species dependent, apparently due to differences in gross, subgross, and cellular respiratory tract biology. Clearance rates for rapidly dissolving particles are not strongly species dependent. Inhalation toxicology studies require several animal species. Rodents are among the most frequently used, but for studies of lung development, diseases, exercise, etc., and for extrapolation to humans, larger mammals are also needed. Fortunately, the research database, and excellent monographs on inhalation phenomena provide ample guidance for study design.