Human cytomegalovirus (HCMV) infection remains one of the most challenging infectious complications in both solid organ transplant (SOT) and hemopoietic stem cell transplant (HSCT) recipients. In the last two decades advances have been made in the diagnosis and monitoring of HCMV infection in SOT and HSCT recipients following introduction of quantitative assays such as rapid virus isolation in blood (viremia), quantitation of pp65 in peripheral blood leukocytes (antigenemia), and quantitation of viral genome in blood (DNAemia). The availability of these rapid diagnostic assays has allowed treatment administration during the presymptomatic phase of HCMV infection (preemptive treatment) and greatly reduced HCMV-related morbidity and mortality, particularly among HSCT recipients. Definition of clinically validated thresholds for initiating preemptive treatment in SOT and HSCT recipients is a major goal in the transplantation setting. With respect to universal prophylaxis of HCMV infection in transplant recipients, the preemptive treatment approach shows advantages in (i) treating a lower number of patients for shorter periods of time and (ii) avoiding the reported emergence of HCMV disease after interruption of anti-HCMV prophylaxis. To understand the mechanism behind long-term control of HCMV infection in transplant recipients, the HCMV-specific T-cell response must be evaluated.