Human Cytomegalovirus (HCMV) is still one of the most concerning infection in transplant recipients. Prevention of clinically relevant HCMV infections depends on HCMV surveillance during the first year after transplantation. Currently, quantification of HCMV DNA in blood samples (HCMV-DNAemia) represents the gold standard for identifying active viral replication, guiding antiviral therapy to prevent HCMV-related disease and monitoring response to drugs targeting HCMV DNA polymerase. While ganciclovir (GCV), valganciclovir (VGCV) and foscarnet (PFA), which are widely used for HCMV therapy, target the viral DNA polymerase (UL54), new antiviral drugs such as letermovir (LTV) and maribavir (MBV) have different targets and mechanisms of action. LTV inhibits the cleavage of viral DNA concatamers and their packaging into virions by targeting the HCMV terminase complex, while MBV interferes with viral pUL97 kinase activity, morphogenesis and nuclear egress of nascent viral particles [1]. In particular, LTV has been proven in a phase-III clinical trial to reduce the risk of clinically significant HCMV infection [2]. Thanks to its safety and lack of myelotoxicity, LTV is approved for prophylaxis in adult haematopoietic stem cell transplant recipients (HSCTR).