Herpes simplex virus (HSV), in contrast to most other members of the herpes virus family, has the ability to infect, enter latency, and reactivate from latency in a number of nonhuman species, including mice. This provides a unique opportunity to study the complex lytic-latent cycle of a human neurotropic virus in a mouse model. This chapter details basic methods for inducing and quantifying reactivation, with emphasis on the first strategy for detecting and quantifying the initiation of HSV reactivation in vivo.