Matched donor-recipient metagenomic sequencing outperformed culture methods in a liver-transplant setting, uncovering possible donor-derived pathogen transmission in most infected recipients. The findings also informed antimicrobial therapy decisions, suggesting sequencing can shift treatment earlier than conventional diagnostics. The study’s practical value lies in reducing uncertainty when cultures fail to detect or time pathogens appropriately. By sequencing matched pairs, teams can better attribute sources of infection rather than treating empirically across multiple possibilities. For transplant programs, the key question will be turnaround time and integration into routine workflows at scale, including how quickly clinicians can act on results to reduce morbidity and improve stewardship.