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Human herpesvirus-6 (HHV-6) frequently reactivates after allogeneic stem cell transplantation (SCT). Most patients are asymptomatic and viremia often resolves without therapy; however, transplant related complications may be associated with reactivation. Multiple presentations have been attributed to HHV-6 reactivation after SCT including encephalitis. Several strategies have been trialed to reduce such risks or complications. Challenges exist with prospective monitoring strategies, and established thresholds of high-level reactivation may be limited. Three published guidelines and extensive trials focusing on pre-emptive and prophylactic strategies are reviewed. Future areas of investigation and high-risk populations are described. Existing trials and testing platforms have significant limitations, and to date no clear benefit for a pre-emptive or prophylactic intervention has been demonstrated.