Lung transplantation is a therapeutic option for patients with end-stage pulmonary disorders. Unfortunately, due to post–lung transplant complications, both infectious and noninfectious, it is only a treatment and not a cure. Importantly, despite induction combined with triple or quadruple maintenance immunosuppressive therapy, chronic lung rejection, in the form of obliterative bronchiolitis or its clinical correlate bronchiolitis obliterans syndrome (BOS), continues to be highly prevalent and is the major limitation to long-term survival. In this review we evaluate the presentation, diagnosis, histopathology, pathologic mechanisms, risk factors, and prevention/treatment options for BOS. A better understanding of the risk factors and how it relates to the pathologic mechanisms of chronic lung allograft rejection should lead to better pharmacologic targets to prevent/treat this syndrome without increasing the recipient's risk for infections.