•Zostavax is a safe vaccine to prevent shingles/postherpetic neuralgia.•Zostavax is a weak stimulator of innate immune responses.•Zostavax changes several metabolomic pathways which are correlated with immune outcome.•Zostavax elicits polyfunctional VZV-specific CD4+ T cells and low CD8+ T cell responses.•Zostavax boosts antibody responses which are strongly influenced by pre-existing antibody levels. Zostavax is a live-attenuated varicella zoster virus (VZV) vaccine recommended for use in adults >50 years of age to prevent shingles. The main risk factor for the development of shingles is age, which correlates with decreasing cell-mediated immunity. These data suggest a predominant role of T cell immunity in controlling VZV latency. However, other components of the immune system may also contribute. In this review, we will discuss how the immune system responds to Zostavax, focusing on recent studies examining innate immunity, transcriptomics, metabolomics, cellular, and humoral immunity.