Varicella-zoster virus (VZV) causes two distinct diseases, varicella (chickenpox) and shingles (herpes zoster). Chickenpox occurs subsequent to primary infection, while herpes zoster (usually associated with aging and immunosuppression) appears as a consequence of reactivation of latent virus. The major complication of shingles is postherpetic neuralgia. Vaccination strategies to prevent varicella or shingles and the current status of antivirals against VZV will be discussed in this chapter. Varivax®, a live-attenuated vaccine, is available for pediatric varicella. Zostavax® is used to boost VZV-specific cell-mediated immunity in adults older than 50 years, which results in a decrease in the burden of herpes zoster and pain related to postherpetic neuralgia. Regardless of the availability of a vaccine, new antiviral agents are necessary for treatment of VZV infections. Current drugs approved for therapy of VZV infections include nucleoside analogues that target the viral DNA polymerase and depend on the viral thymidine kinase for their activation. Novel anti-VZV drugs have recently been evaluated in clinical trials, including the bicyclic nucleoside analogue FV-100, the helicase-primase inhibitor ASP2151, and valomaciclovir (prodrug of the acyclic guanosine derivative H2G). Different candidate VZV drugs have been described in recent years. New anti-VZV drugs should be as safe as and more effective than current gold standards for the treatment of VZV, that is, acyclovir and its prodrug valacyclovir.