Lung transplantation is the only therapeutic option for patients with end-stage pulmonary disorders. Despite the improvements in surgical techniques and immunosuppressive therapy, allograft function and long-term survival are limited by the development of chronic lung transplant rejection. In this review, we focus on bronchiolitis obliterans syndrome (BOS) which is the major manifestation of chronic lung allograft rejection. We specifically review the effect of infection, a risk factor for BOS, cytokines/chemokines in the pathogenesis of BOS, and the potential link between the allograft microbiome and immune responses that may mediate the development of BOS. Understanding the allograft microbiome and how it relates to the pathologic mechanisms of BOS may suggest targeted therapies to improve long-term survival post-lung transplantation.