Varicella-zoster virus (VZV) is highly species-specific and has been demonstrated to naturally infect only humans and great apes. Simian varicella, a group of antigenically related agents distinct from VZV, infects cercopithecoids producing severe varicella-like disease but does not infect humanoids. Seroconversion following inoculation of VZV in small laboratory animals has been demonstrated in the rat, rabbit, and guinea pig; however, animal-to-animal spread, viremia, and exanthem have been demonstrated only in guinea pigs. Both humoral and cellular immune responses to VZV infection have also been examined in the guinea pig model. Ocular infection with VZV has been explored in both the guinea pig and rabbit. Animal models of VZV persistence have been elusive although persistence may be established in the rat.