Early observations following transplantation of the heart and both lungs have suggested that acute rejection occurs simultaneously in both organs. Endomyocardial biopsy could, therefore, be used to monitor rejection in both heart and lungs. We present here our experience with heart-lung transplantation in the baboon, and in two recently observed human patients. The evidence we provide suggests that acute rejection may occur earlier in the lungs than in the heart, and that monitoring the heart alone may prove inadequate. Of 12 baboons that survived heart and lung transplantation, 11 died from acute isolated pulmonary rejection; 10 of these 11 animals showed no features of cardiac rejection. In 2 of 6 human patients who have undergone this operation, an episode of acute pulmonary rejection is believed to have occurred in the absence of cardiac rejection. There is no 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 be directed toward developing tests that indicate acute rejection but are not organ specific, rather than relying on techniques that diagnose cardiac rejection only. © 1986, The Society of Thoracic Surgeons. All rights reserved.