Once an individual is infected with herpes simplex virus (HSV), the virus establishes a latent infection in sensory neurons. Periodically, various stimuli may induce lytic reactivation resulting in mild recurrent lesions to more severe disease. The factors which determine the establishment of latency and reactivation are poorly understood. However, considering the requirements for the viral IE gene products in productive infection, it is likely that the regulation of this latency/reaction cycle is dependent upon the components which regulate the expression of the IE genes. The critical component of this regulatory process is HCF-1. Analyses of this protein in a mouse model have shown that the protein is specifically sequestered in the cytoplasm of sensory neurons and rapidly transported to the nucleus in response to reativation stimuli. Additional studies have determined (i) transport of the factor is directly correlated with neurons undergoing viral reactivation; and (ii) distinct reactivation stimuli result in transport. Studies which focus on another component involved in the regulation of the IE genes (Oct-1) have indicated that this protein, in contrast to the accepted model, is not required for the induced expression of the IE genes. This suggests that there are alternative regulatory mechanisms mediated by other components that can play a significant role in the induction of the IE genes. The data has led to the model that distinct reactivation stimuli may result in different induction mechanisms that may be mediated by the common critical component HCF-1.