Herpes simplex virus (HSV) serotypes 1 and 2 are among the most widespread human viruses. HSV disease has a complex phenotype, with symptoms that can range from mild lesions to encephalitis. In the clinical setting, this diversity of outcomes poses a major challenge, making timely disease diagnosis and treatment challenging. High-throughput sequencing (HTS) has been one of the breakthrough technologies in the modern era of molecular biology, and it is revolutionizing the study of pathogen biology and clinical diagnostics. Here, we review recent studies that have used HTS to answer questions related to the evolution of drug resistance, transmission and spread, virulence marker identification, and the design of better antiviral therapeutics for HSV. We also highlight practical considerations for handling computational analysis of HSV genomes and adoption of HTS as a routine diagnostic procedure in the clinical laboratories.