The earliest interactions between viruses and host cells are critical to determining the outcome of infections. The interactions between a virus and its host cells that lead to the production of inflammatory cytokines are essential to the development of T cells and antibodies that provide long-term defense against the invaders. At the same time, however, these same cytokines (or sometimes other mediators or chemokines) stimulate inflammation, which may lead to localized tissue damage and/or systemic circulatory collapse and death. This review focuses on the interaction between Toll-like receptors, a critical component of the innate immune system of mammals, and their role in herpes simplex pathogenesis and immunity.