The reliability of bronchoscopy with transbronchial biopsies for the diagnosis of acute graft rejection has recently been questioned. We present our experience with 59 transbronchial and bronchial biopsies and two open-lung biopsies from 12 patients that underwent lung transplantation. The diagnosis of acute rejection was established in 14 biopsies based on the absence of infection and presence of one or more of the following features: perivascular lymphoid infiltrates, usually associated with endothelial swelling; bronchial "acute on chronic" inflammation; and/or angiitis. Problems and potential pitfalls in the diagnosis of acute graft rejection in lung transplant patients are discussed. The biopsies were also sensitive for the diagnosis of cytomegalovirus pneumonitis and fungal infections but were not helpful for the diagnosis of bacterial pneumonias. Indeed, one patient died with Legionella sp. pneumonia diagnosed only on open-lung biopsy after two negative transbronchial biopsies. The significance of other histologic changes, such as nonspecific interstitial pneumonitis, diffuse alveolar damage, acute alveolitis, goblet cell hyperplasia of the bronchial mucosa, and pulmonary infarction, is discussed.