PURPOSE OF REVIEW: Technology to rapidly determine the partial or full genomic sequences of large viruses has developed rapidly in the last few years. Required sample sizes have diminished and sequencing of directly collected patient samples is now possible. Using banked samples from a number of clinical studies researchers have investigated how genomic variation may determine pathogenicity and answering important questions around the limits of vaccine therapy. RECENT FINDINGS: The natural variation in HSV-1 and HSV-2 geographically has been determined. Variation in the genes responsible for surface glycoproteins may explain the current limitations of therapy. Studies looking at genomic sequences for HSV-2 in subjects with recurrent disease and in those who took part in failed vaccine studies show that multiple HSV-2 strain infection is rare outside Africa and in those with immunodeficiency, whereas there is no evidence that vaccination drives viral evolution. Genome wide association studies have investigated rates of HSV shedding have failed to identify the link between subject genomic sequence and the severity. SUMMARY: These studies will help develop better diagnostics and vaccines that are likely to be more widely effective. The findings will help counsel patients. The factors determining HSV disease severity in individuals remain elusive.