The recent approval of letermovir marks a new era of therapy for human cytomegalovirus (HCMV) infections, particularly for the prevention of HCMV disease in hematopoietic stem cell transplant recipients. For almost 30 years ganciclovir has been the therapy of choice for these infections and by today's standards this drug exhibits only modest antiviral activity that is often insufficient to completely suppress viral replication, and drives the selection of drug-resistant variants that continue to replicate and contribute to disease. While ganciclovir remains the therapy of choice, additional drugs that inhibit novel molecular targets, such as letermovir, will be required as highly effective combination therapies are developed not only for the treatment of immunocompromised hosts, but also for congenitally infected infants. Sustained efforts, largely in the biotech industry and academia, have identified additional highly active lead compounds that have progressed into clinical studies with varying levels of success and at least two have the potential to be approved in the near future. Some of the new drugs in the pipeline inhibit new molecular targets, remain effective against isolates that have developed resistance to existing therapies, and promise to augment existing therapeutic regimens. Here, we will describe some of the unique features of HCMV biology and discuss their effect on therapeutic needs. Existing drugs will also be discussed and some of the more promising candidates will be reviewed with an emphasis on those progressing through clinical studies. The in vitro and in vivo antiviral activity, spectrum of antiviral activity, and mechanism of action of new compounds will be reviewed to provide an update on potential new therapies for HCMV infections that have progressed significantly in recent years.