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Human herpesvirus 6 (HHV-6) frequently reactivates after solid-organ and hematopoietic cell transplantation (HCT), and it has been associated with important outcomes in these settings. In 1–2% of recipients or donors, HHV-6 was inherited through chromosomal integration. Although HHV-6 chromosomal integration has not been associated with disease, the resulting very high levels of HHV-6 DNA in human tissue and blood samples can be challenging to interpret in the transplant setting. This review addresses the recent findings regarding the clinical outcomes associated with HHV-6 as well as diagnostic and therapeutic concerns.The evidence supports a causal association between HHV-6 and central nervous system disease. New studies have further characterized the impact of HHV-6 on the central nervous system. In addition, new studies have explored the associations between HHV-6 and other important outcomes. The implications of integrated HHV-6 in transplant recipients remain undefined, though the possibility of an association with organ rejection has been suggested. New exploratory data exist regarding the safety of antiviral prophylactic and preemptive strategies.Our understanding of the full clinical impact of HHV-6 in the transplant population remains incomplete. A large antiviral trial would not only help to further define causality between HHV-6 associated clinical outcomes but also start to define preventive strategies.