Here, we show that organ-specific donor DNA is detectable in the plasma of heart transplant recipients and that this genetic signature increases substantially before rejection events. We also demonstrate a universal, sex-independent strategy using shotgun sequencing to measure single nucleotide polymorphism (SNP) differences between individuals to quantify the donor DNA signal. This genome transplant dynamics (GTD) approach is applicable to any organ donor and any recipient, regardless of sex, by first genotyping the donor and recipient to establish a unique donor “genetic fingerprint,” which can be detected by high throughput sequencing of cell-free DNA in the recipient's blood following transplantation. The GTD assay provides a quantitative measure of organ health that can complement or possibly replace other approaches for posttransplant monitoring.