Human cytomegalovirus (HCMV), a member of the betaherpesvirinae, can cause life-threatening diseases. HCMV is globally widespread, with a seroprevalence in adults varying from 50 to 100%. HCMV infection is rarely of significant consequence in immunocompetent individuals. However, although immune control is efficient, it cannot achieve the clearance of the virus. HCMV persists lifelong in the infected host and reactivates in certain circumstances. In neonates and in immunocompromised adults, HCMV is a serious pathogen that can cause fatal organ damage. Different antiviral compounds alone or in combination have been used for the treatment of HCMV diseases. In clinical use, mutations in the viral DNA polymerase or the terminase confer resistance to ganciclovir, foscarnet, cidofovir, and letermovir. There is an urgent need to find new well-tolerated compounds supporting different modes of action. The list of novel small molecules that might have anti-HCMV activity has grown in recent years. In this short review, a selection of compounds in clinical trials and novel inhibitors targeting host-cell factors or viral proteins is presented, and their modes of action, described.