Varicella zoster virus (VZV) is a highly neurotropic, exclusively human herpesvirus. Primary infection causes varicella (chickenpox), wherein VZV replicates in multiple organs, particularly the skin. Widespread infection in vivo is confirmed by the ability of VZV to kill tissue culture cells in vitro derived from any organ. After varicella, VZV becomes latent in ganglionic neurons along the entire neuraxis. During latency, virus DNA replication stops, transcription is restricted, and no progeny virions are produced, indicating a unique virus-cell (neuron) relationship. VZV reactivation produces zoster (shingles), often complicated by serious neurological and ocular disorders. The molecular trigger(s) for reactivation, and thus the identity of a potential target to prevent it, remains unknown due to an incomplete understanding of the VZV-neuron interaction. While no in vitro system has yet recapitulated the findings in latently infected ganglia, recent studies show that VZV infection of human neurons in SCID mice and of human stem cells, including induced human pluripotent stem cells and normal human neural progenitor tissue-like assemblies, can be established in the absence of a cytopathic effect. Usefulness of these systems in discovering the mechanisms underlying reactivation awaits analyses of VZV-infected, highly pure (>90%), terminally differentiated human neurons capable of prolonged survival in vitro.