Male Lewis rats pretreated by inhalation of an atmosphere containing 1.6 mg Cd/m3 for 4 weeks (3 hr/day, 5 days/week) exhibited pulmonary tolerance when challenged with a single 3-hr acute exposure to 8.4 mg Cd/m3. Tolerance in prior-exposed animals was suggested by (a) bronchoalveolar lavage fluid analysis showing a reduction in the number of inflammatory cells and decreased release of lactic dehydrogenase, alkaline and acid phosphatase, and protein into the alveolar space and (b) an earlier resolution in lung histopathology following Cd challenge compared to sham air control animals. Multiple defense mechanisms appear to be involved in the development of pulmonary tolerance to Cd. Metallothionein (MT) content in lungs of prior-exposed animals was 50-fold higher than that in untreated animals. The amount of Cd retained in the lungs after the challenge dose was the same regardless of whether the animals had been pretreated with Cd. However, the Cd/thionein ratio was considerably lower in treated animals and did not increase upon challenge, suggesting that synthesis of MT was keeping abreast with the amount of accumulated Cd. Pretreatment of animals with Cd aerosols also led to an increase in the number of type II alveolar cells which may, in turn, be responsible for increasing nonprotein sulfhydryl groups and antioxidant enzymes in the lung.