There is extensive anecdotal evidence supporting an association between psychological stress and one's susceptibility to a variety of infectious pathogens. These pathogens include a number of viruses with significant short- and long-term health consequences. Infections with one such virus, herpes simplex virus (HSV), have long been recognized to be linked to a variety of life stressors. These HSV infections, both primary and recurrent, have been thought to be, in part, a function of a decreased immune surveillance and a suppression of antiviral immune defense mechanisms. Such stress-induced alterations in immune capacity may be mediated by one or more products of the nervous and endocrine systems.A number of human and animal studies have provided data to support this hypothesis and represent a subset of a larger group of studies that have established a solid link among psychological stress, immune function, and diseases caused by pathogenic microorganisms (reviewed in Moynihan and Ader, 1996; Sheridan et al., 1998; Bonneau et al., 2001; Bailey et al., 2003; Moynihan and Stevens, 2004). Recent advances in experimental immunology have broadened our knowledge of immunological processes that, in turn, have facilitated the design of studies to better examine the interactions among the nervous, endocrine, and immune systems at both the cellular and molecular levels. The information provided in this chapter will review some of the studies that have established a link between stress and HSV, and the impact of this link on human health will be discussed.