Live, attenuated Oka/Merck varicella-zoster virus (VZV) vaccine (zoster vaccine) protects immunocompetent adults from herpes zoster and its complications. Success of zoster vaccine in preventing the clinical manifestations of latent VZV reactivation contrasts with the failure to achieve similar results with vaccination to prevent recurrent herpes simplex. This reflects major differences in the pathophysiology of latency and reactivation of these 2 alphaherpesviruses. The Shingles Prevention Study and many others have demonstrated that VZV-specific cell-mediated immunity, but not VZV antibody, plays a critical role in limiting reactivation and replication of latent VZV and, thus, in preventing herpes zoster and its complications. Consequently, induction of VZV-specific cell-mediated immunity and not antibody should be used as a proxy for the clinical efficacy of new formulations and uses of zoster vaccine. Prospects for improved zoster vaccines and their use in immunocompromised patients are discussed, and questions related to zoster vaccine use are addressed.