Herpes simplex virus-2 (HSV-2) is periodically shed throughout the human genital tract. Although a high viral load correlates with the development of genital ulcers, shedding also commonly occurs even when ulcers are absent, allowing for silent transmission during coitus and contributing to high seroprevalence of HSV-2 worldwide. Frequent viral reactivation occurs within ganglia despite diverse and complementary host and viral mechanisms that predispose toward latency, suggesting that viral replication may be constantly occurring in a small minority of neurons at these sites. Within genital mucosa, the in vivo expansion and clearance rates of HSV-2 are extremely rapid. Resident dendritic cells and memory HSV-2 specific T cells persist at prior sites of genital tract reactivation and, in conjunction with prompt innate recognition of infected cells, lead to rapid containment of infected cells. The fact that immune responses usually control viral replication in genital skin before lesions develop provides hope that enhancing such responses could lead to effective vaccines and immunotherapies.