We examined the utility of the transbronchial biopsy in the management of 53 lung transplant patients. One hundred thirty-three protocol biopsies were performed to ascertain the frequency and nature of abnormalities in clinically stable or asymptomatic patients; 128 diagnostic biopsies were performed in clinically ill patients to assess the morphologic abnormalities before the institution of therapy, and 105 biopsies were performed to assess the response to therapy. Histologic evidence of acute rejection was found in 24% of the protocol biopsies, and infection was found in 17%. Twenty-five patients with grade 1 or grade 2 perivascular infiltrates in protocol biopsies did not receive antirejection therapy. Follow-up biopsy in these patients showed spontaneous resolution of the infiltrates in 19% and increased infiltrates in 6. Only two of these patients became clinically ill, representing "progression" to clinical rejection in only 8% of the nontreated patients. Forty percent of the biopsies performed to rule out acute rejection or infection had histologic features of acute rejection, and another 23% had features of infection. Treatment of patients with clinical and histologic evidence of rejection was associated with rapid resolution of clinical symptoms in nearly 90% of the patients, but follow-up biopsies showed residual infiltrates compatible with ongoing or resolving rejection in 52%. Despite repeat antirejection therapy in some patients, these infiltrates persisted for an average of 30 days after the diagnostic biopsy. Follow-up biopsies also showed asymptomatic infection, usually cytomegalovirus pneumonitis, which often persisted for weeks despite the lack of symptoms. Perivascular infiltrates compatible with acute rejection were also found in 38% of biopsy specimens with evidence of infection. These perivascular infiltrates resolved with antibiotic treatment alone in nearly 50% of the patients with these features. Although perivascular mononuclear cell infiltrates are the cardinal histologic feature of acute rejection, similar infiltrates occur in patients who apparently have infection alone and other patients who have both infection and rejection; infiltrates compatible with minimal, mild, and moderate acute rejection also occur in clinically asymptomatic patients. These histologic findings are a challenge to both the pathologists' and the clinicians' skills in the management of the lung transplant patient.