Although the clinical significance of anti-HLA antibodies in heart and lung transplantation is less well studied than in renal transplantation, several studies have shown that heart and lung recipients transplanted in the presence of donor-specific antibodies are at increased risk for early acute rejection and have a lower graft survival. In an effort to avoid any increase in organ ischemia time, heart and lung candidates with anti-HLA antibodies have to be identified prior to transplantation and crossmatches performed with donor materials obtained prior to organ recovery. Both class I and II antibodies have been found to be associated with chronic rejection, defined in heart transplantation as transplant-related coronary artery disease (TRCAV) and in lung transplantation as obliterative bronchiolitis (OB) or bronchiolitis obliterative syndrome (BOS). Post-transplant de novo development of donor antigen-specific class II antibodies has been found to be especially deleterious, significantly increasing the risk of chronic rejection and poor graft outcome. Based on the review of studies regarding the development of anti-HLA antibodies and thoracic organ allograft rejection several conclusions can be drawn. The presence of class I and II-directed anti-HLA antibodies, detected by any method, are associated with acute and chronic rejection in heart and lung transplantation. Different therapeutic strategies have been used pre-transplantation to decrease the level of anti-HLA antibodies and post-transplantation to maintain low antibody levels or treat rejection, thereby improving graft outcome. Thus, monitoring the presence and the level of anti-HLA antibodies is prognostic of graft outcome and allows for measurement of therapeutic efficacy.