Considerable research has established an association between human leukocyte antigen antibodies and chronic rejection. Two new major developments now provide evidence that this relationship is in fact causative. First, recent studies of serial serum samples of 346 kidney transplant patients from four transplant centers show that de novo antibodies, can be detected before rejection. Moreover, serial testing revealed that when antibodies were not present, 528 patient years of good function was demonstrable in 149 patients. Second, among 90 patients whose grafts chronically failed, 86% developed antibodies before failure. To assess the likelihood of a causal link, we applied the nine widely accepted Bradford Hill criteria and conclude that the evidence supports a causal connection between human leukocyte antigen antibodies and chronic rejection. The clinical implication is significant because we hope this review will stimulate centers to begin the one remaining task of showing that antibody removal will indeed prevent chronic failure.