Allogeneic hematopoietic cell transplants (allo-HCT) recipients are at the high-risk of reactivation of cytomegalovirus (CMV), and reactivation is associated with significant morbidity and mortality. Although available anti-CMV therapies may be effective for the prevention of CMV, they are plagued by unacceptable toxicities that prohibit their use in the post-transplant period. Recently studied CMV-active agents, such as maribavir and brincidofovir, failed to reduce the incidence of CMV infection in HCT recipients. Letermovir represents the first agent in the non-nucleoside 3,4 dihydro-quinazoline class of CMV viral terminase complex inhibitors, with activity solely against CMV. The positive results from the recently published Phase III study of letermovir for prevention of CMV infection in CMV-seropositive allo-HCT recipients led to its approval as a prophylactic agent for CMV in multiple countries. Areas covered: In this review, we will evaluate this novel agent with a focus on letermovir mechanism of action, pharmacokinetics and metabolism, clinical efficacy, and safety and toxicities. Expert commentary: With the introduction of letermovir, prevention of CMV infection in allo-HCT recipients may shift considerably, from a predominantly preemptive strategy to one that utilizes this novel therapy for prophylaxis.