Organ transplantation is an effective treatment for several end-stage organ diseases. Preventing rejection of transplanted organs remains the premier challenge. According to the humoral theory, donor specific antibodies (DSA) are the major cause of chronic rejection and allograft loss. Despite this, and evidence that links human leukocyte antigen (HLA) antibodies to allograft dysfunction and loss, doubt remains about the cause-and-effect relationship and confirmation of this evidence is necessary to help facilitate change in transplant practice. Prospective monitoring for de novo DSA in the serum of patients who have received a transplant may allow for earlier detection, evaluation, and characterization of factors leading to the development of antibodies prior to the development of clinical manifestations of graft dysfunction.