The term "chronic lung allograft dysfunction" has emerged to describe the clinical syndrome of progressive, largely irreversible dysfunction of pulmonary allografts. This umbrella term comprises 2 major clinical phenotypes: bronchiolitis obliterans syndrome and restrictive allograft syndrome. Here, we discuss the clinical manifestations, diagnostic challenges, and potential therapeutic avenues to address this major barrier to improved long-term outcomes. In addition, we review the immunologic mechanisms thought to propagate each phenotype of chronic lung allograft dysfunction, discuss the various models used to study this process, describe potential therapeutic targets, and identify key unknowns that must be evaluated by future research strategies.