VZV is a ubiquitous human pathogen typically encountered early in life when primary infection causes chickenpox. During this time the virus infects ganglionic neurons at all levels of the neuraxis where the virus remains latent in host neurons. The fact that 495% of the world’s inhabitants have an immunologic response to VZV highlights the problem encountered when ascribing disease etiology to VZV reactivation. There are multiple challenges and problems to better understand pathobiology of VZV latency. There is currently no suitable disease model that mirrors the human diseases caused when virus reactivates. Without a disease model, Koch’s postulates cannot be met and ascribing a causal relationship is tenuous. Without a suitable model for all facets of VZV infection, latency and reactivation, understanding of VZV pathobiology will be difficult.