Accurate and timely diagnosis of rejection and infection is essential for long-term survival of solid-organ transplant recipients. We evaluated the performance a novel test to monitor rejection and infection through shotgun sequencing of plasma-derived cell-free DNA. We show that an elevated level of donor-derived cell-free DNA correlates with indicators of graft dysfunction and rejection in heart and lung transplantation. We also find a strong correlation between clinical test results and cell-free DNA derived from cytomegalovirus (CMV), the primary infectious disease complication for transplant recipients. We further show that cell-DNA can be used to detect and monitor pathogens that are not routinely screened in the clinic and we show that the composition of viral sequences is highly dynamic and strongly affected by immunosuppressive and antiviral drugs.