The major challenges to success in the modern era of lung transplantation are the problems of graft infection and rejection. The lung is the only solid organ in which infection is virtually guaranteed after transplantation. Clinical management of lung transplantation candidates includes testing for previous and current infections and appropriate immunizations. An aggressive prophylactic regimen against infection after lung transplantation is tailored to the individual patient's underlying disease and infection history. A high index of suspicion and frequent testing, including rapid viral diagnosis and flexible fiberoptic bronchoscopy with bronchoalveolar lavage, have become the standard in posttransplantation medical management. The problems of acute and chronic graft rejection seem to be more frequent and severe in lung transplant recipients than in those who receive other solid organ transplants. Anticipation and aggressive treatment of early acute graft rejection are critical aspects of the care of patients in the first months after transplantation. Bronchiolitis obliterans, which is caused by chronic graft rejection, is the biggest obstacle to long-term survival. New diagnostic and therapeutic strategies to detect and treat the infectious and immunologically mediated complications of lung transplantation will be needed in the future.