Human cytomegalovirus (HCMV) infections are usually benign and self-limiting in the immunocompetent population; however, HCMV is a well-recognized problem among immunocompromised patients (in particular immunosuppressed patients with stem cell or solid organ transplantation, AIDS, or cancer). In this group of patients, HCMV infections are a significant cause of morbidity and mortality. Additionally, congenital HCMV infections are a leading cause of birth defects and infections in children, occurring in 1 to 2% of all live births. Currently available drugs for the treatment of HCMV diseases in the immunocompromised host include ganciclovir (GCV), its oral prodrug valganciclovir (VGCV), cidofovir (CDV), foscavir (FOS), and fomivirsen. Except for fomivirsen, all these drugs are targeted at the viral DNA polymerase. Even if presently approved anti-HCMV drugs have considerable helped in the management of HCMV disease in the immunocompromised host, their use is limited due to questions of toxicity, poor oral bioavailability, modest efficacy, and development of virus-drug resistance. Furthermore, no drug has been licensed to treat congenital HCMV. For these reasons, there is a real need to develop new compounds active against HCMV. The search for novel inhibitors of HCMV replication has led to the identification of new molecular viral targets such as the protein kinase UL97 and proteins involved in genome replication or in viral maturation and egress. Moreover, a new strategy based on the identification of specific cellular targets required for viral replication has been developed. This review will focus on new compounds that inhibit a specific viral process (viral targets) and on cell-based approaches (cellular targets) that result in selective inhibition of virus replication.