Herpesvirus proteases have emerged as targets for the development of novel antiviral drugs. These enzymes, which are necessary for the replication of all herpesviruses, are serine proteases, but possess a unique structure as revealed by solution of the crystal structure of human cytomegalovirus protease. Many of the biochemical properties of these enzymes are now explained by the structure. Conventional serine protease inhibitors are not potent inhibitors of these enzymes and therefore the search for potent inhibitors possessing necessary features of an effective antiviral will require novel approaches. The three-dimensional structure serves as a milestone for continued endeavors towards this goal.