The herpesviruses are an exceptionally interesting pathogen and the cause of lifelong infection for more than 90% of the human population. They are also a significant cause of morbidity and mortality with limited treatment options; many herpesviruses have no approved treatment and all approved treatments target the same viral enzyme suffering from resistance and toxicity. This text begins with a review of both the biology and the current and future treatment options for the nine human herpesviruses. Particular emphasis is placed on the herpesvirus proteases as potential therapeutic targets, the focus of the remaining 8 chapters. I report high throughput screening (HTS) assays and results for standard HTS, fragment-based screening, and disulfide tethering identifying novel inhibitors of both Kaposi’s sarcoma-associated herpesvirus (KSHV) and cytomegalovirus (CMV) proteases. Detailed structural analysis reveals at atomic level the unique mode of binding for a subset of dimer disruptors—protein-protein interaction antagonists that bind a transient cryptic pocket at the dimer interface thereby allosterically inhibiting the active site. Kinetic analysis shows that these analogs are slow time-dependent inhibitors, a fact that could aid in achieving cellular efficacy. Finally I detail our first evidence of a dimer disruptor successfully inhibiting viral reinfection in human cells. As a whole, this text provides a powerful case study of developing a protein-protein interaction antagonist against a highly dynamic essential viral protein and advances progress toward novel methods of herpesvirus inhibition.