Herpes simplex viruses are evolutionarily ancient and ubiquitous. In the past 20 years, there has been increasing recognition of a worldwide pandemic of HSV-2 infection. Moreover, HSV-2 prevalence has increased despite fairly widespread use of antiviral drugs for HSV. The success of HSV-1 and HSV-2 stems from latency within long-lived neurons and frequent mucocutaneous shedding. The generally mild medical consequences of HSV infection reflect a functional equilibrium between host and microbe in most immunocompetent persons. However, significant gaps in our knowledge of the correlates of disease severity and HSV immune evasion are limiting rational advances in these areas. Human genetic studies are gradually outlining important innate responses, while recent imaging and biopsy studies have begun to show that the temporal and spatial anatomic interplay between virus reactivation and host immune response may be important in reactivations and disease expression.