Lung transplantation is recognized as a viable treatment option in a variety of end-stage pulmonary diseases. However, the long-term survival is limited by the development of bronchiolitis obliterans syndrome (BOS). Bronchiolitis obliterans syndrome occurs in more than half of lung transplant recipients who survive more than 5 years and is the leading cause of death in the late posttransplantation period. The specific etiology and pathogenesis of BOS are not well understood. The current premise is that BOS represents a common lesion in which different inflammatory insults such as ischemia-reperfusion, rejection, and infection can lead to a similar histological and clinical outcome. However, the observation that early development of BOS is predicted by the frequency and severity of acute rejection episodes indicates that alloimmune-dependent mechanisms play a crucial role in the pathogenesis of BOS. The evidence presented in this review will demonstrate that BOS is the result of indolent humoral immune responses developed against major histocompatibility complex molecules expressed by airway epithelial cells of the lung allograft. Currently, treatment of BOS is rarely successful. Therefore, a better understanding of the immunopathogenesis of BOS is of paramount importance toward improving long-term graft function and patient survival after lung transplantation.