Background Lung transplantation is a therapeutic option for select patients with end-stage lung disease. However, successful lung transplantation is hampered by chronic lung allograft dysfunction, in particular bronchiolitis obliterans syndrome (BOS). Although there is no approved or standard treatment for BOS, which may have several distinct phenotypes, extracorporeal photopheresis (ECP) has shown promising results in patients who develop BOS refractory to azithromycin treatment. Methods We reviewed all relevant clinical data indexed on PubMed from 1987 to 2017 to evaluate the role of ECP in patients with BOS. Results Seven small studies investigated the immunomodulatory effects of ECP in patients after solid organ transplant, and 12 studies reported clinical data specific to ECP therapy for BOS. Studies indicate that ECP triggers an apoptotic cellular cascade that exerts various immunomodulatory effects mediated via increases in anti-inflammatory cytokines, a decrease in proinflammatory cytokines, and an increase in tolerogenic regulatory T cells. Clinical evidence derived from relatively small single-center studies suggests that ECP therapy is associated with improvement or stabilization in lung function and sustainable, statistically significant, decreases in the rate of lung function decline in patients with BOS. Additionally, when adverse event data were reported, ECP was generally well tolerated. None of the comparative studies were randomized. Conclusions Immunomodulation mediated via ECP is a rational therapeutic option that may improve clinical outcomes in patients with BOS, particularly in the context of in-depth patient phenotyping as part of a stratified approach to treatment; good quality randomized controlled trials are needed to confirm observational findings.