Acute infection of a permissive host by a α-herpesvirinae subfamily member leads to expression of all viral genes and high levels of virus shedding. Following acute infection, most α-herpesvirinae subfamily members establish and maintain life-long latency in sensory neurons. In contrast to productive infection during acute infection or infection of permissive cultured cells, viral gene expression is limited to the latency-associated transcript locus. The ability of these viruses to periodically reactivate from latency is crucial for virus transmission and recurrent disease is due to reactivation from latency. For example, herpes simplex virus type 1 (HSV-1) and HSV-2 are important human pathogens that cause recurrent eye disease, including blindness, and recurrent genital infections, respectively. External stressors disrupt the maintenance of latency and increase the incidence of reactivation from latency. Regardless of their mechanism of action, external stressors that promote reactivation from latency must initiate expression of key regulatory viral genes in latently infected neurons. Most external stressors that induce reactivation also suppress immune responses. The viral and cellular factors that regulate reactivation from latency and recurrent disease are discussed in this review.