Since the 1950s, herpes simplex viruses (HSV) have played prominent roles in the development of antivirals. The first efficacious antivirals, as well as the first safe for systemic use, were developed against HSV. It was only in 1995 when the first antiviral against a target not validated first with HSV was approved for clinical use (sequinavir). The early successes of targeting HSV DNA replication were most influential in developing the concept that antiviral drugs must target viral proteins. Such concept has ensured the safety of current antiviral drugs, which all target viral proteins. Current antivirals have proven to have no major negative effects on non-infected cells or treated patients. Because of their success widespread and use, however, these drugs have been found to have some limitations. Perhaps the clinically most important one is their ability to promptly select for drug-resistant viral strains. Owing to such limitations, cellular proteins are now considered as valid targets for novel antiviral drugs. The discovery that pharmacological CDK inhibitors (PCIs) inhibit HSV replication through novel mechanisms played a major role in this new appreciation of cellular proteins as potential targets for antivirals. This appreciation is reflected in the scheduling of PCIs to enter clinical trials as antivirals (against HIV). Herein, we will review the roles of HSV as model viruses in the discovery and development of antiviral drugs. The major focus will be on the recent discovery on the activities of PCIs against HSV and other viruses.