Twelve Chacma baboons underwent transplantation of the heart and both lungs from donor baboons matched for size and AB blood group. Cyclosporine was given daily orally, by twice daily intravenous injections, or by a single intravenous injection (together with oral azathioprine and, after 2 weeks, methylprednisolone); whole blood trough levels were inadequate in all groups. Survival was from 4 to 29 days, with death resulting from acute rejection of the lungs in 11 and from bronchopneumonia in one. In the 11 animals dying from rejection, histologic examination showed that the heart was spared from severe rejection in all cases but one. In the inadequately immunosuppressed baboon, therefore, acute rejection occurs earlier in the lungs than in the heart. We have now observed what we believe to have been acute pulmonary rejection in the absence of cardiac rejection on five occasions in three patients in our clinical transplantation program. We would suggest that pulmonary rejection must always be strongly suspected if there are any suggestive features, particularly pulmonary shadowing on chest radiographs, despite negative results of tests indicating rejection of the heart. In the absence of any easy method of confirming pulmonary rejection directly (other than open-lung biopsy, which is clearly contraindicated as a routine procedure), we suggest that more attention should be directed toward developing tests for rejection that are not organ specific, rather than relying on techniques that diagnose cardiac rejection only.