 Acute rejection AR occurs within the first 6 months after transplantation in 20 percent of heart-transplant patients and in 50 percent of lung-transplant patients. Given the often silent clinical presentation of AR, these patients require monitoring with repeated invasive and costly endomyocardial EMB or transbronchial biopsies TBBx. Since organ transplantation is essentially genomic transplantation, our prior studies leveraged the use of distinctive graft and recipient genotype single-nuclear polymorphisms SNPs to barcode donor DNA circulating in recipient serum. We have shown that levels of donor DNA measured as the percentage of circulating cell-free donor-derived DNA ccfdDNA correlates with AR diagnosis and severity as detected by biopsy. The performance receiver operator curve ROC of ccfdDNA yielded an area under the curve AUC of 0.83. Using this technique, we can diagnose AR by measuring elevations in ccfdDNA up to 5 months before EMB-detected pathology. While these findings suggest that monitoring ccfdDNA may offer a high-performing, non-invasive, and early diagnostic tool of AR, further validation studies are required to determine its clinical utility. The ability to diagnose AR earlier than possible with a biopsy offers an opportunity to investigate the pathogenesis of rejection as well as to identify potential AR biomarkers. Thus, the primary objective of this study is to validate the predictive accuracy and ROC characteristics of ccfdDNA for AR in a multicenter, prospective cohort study of heart- and lung-transplant patients, recruited through a consortium of 5 transplant centers in the Washington, DC metropolitan area. The secondary objectives are: 1 to compare ccfdDNA characteristics in AMR antibody-mediated rejection and ACR acute cellular rejection, and 2 to study early immunological changes associated with a significant rise in ccfdDNA, and 3 to determine the association between early graft injury caused by acute rejection and infecton and the development of chronic refection. 