The respiratory tract is a complex organ system both macroscopically and microscopically, with many different functions and cell types localized throughout the nasopharyngeal, tracheobronchial, and pulmonary segments. Exposure to xenobiotics occurs via inhalation and via the blood following ingestion, dermal exposure, or parenteral administration. Xenobiotics vary from particles of variable size to gases to plant toxins, thus dosimetry and site of injury are critical in interpreting the response to injury. In addition, species differences must be considered in interpretation of data to be used in risk assessment. In naturally occurring disease, since the pulmonary response to injury is often non-specific, it is important to consider the gross distribution of pulmonary lesions and to use detailed history and ancillary test results in conjunction with histological evaluation to determine potential etiologic agents.