Bronchiolitis obliterans syndrome (BOS) is the leading cause of death beyond the first year after lung transplantation. The development of antibodies to human leukocyte antigens (HLA) after transplantation has been recognized as an independent risk factor for BOS development. To review the literature on the potential role of HLA antibodies on BOS development and other outcomes after lung transplantation, a MEDLINE search was performed. Multiple retrospective clinical studies from different centers have identified the development of HLA antibodies as a significant and independent risk factor for BOS. In addition, HLA antibodies have been linked to an increased risk of acute rejection and lymphocytic bronchiolitis. Furthermore, experimental studies suggest that HLA antibodies have a pathogenic role in BOS development and are not merely an epiphenomenon of cellular immunity. Lastly, findings from a single-center study suggest that the early depletion of HLA antibodies may mitigate the risk of BOS. HLA antibodies clearly play an important role in lung allograft rejection, and early antibody depletion may favorably influence clinical outcomes. However, future research will need to corroborate the benefits of antibody-directed therapy before this approach becomes widely accepted.