Silver nanoparticles (AgNP) are used in multiple applications but primarily in the manufacturing of antimicrobial products. AgNP toxicity in the respiratory system is well characterized, but few in vitro or in vivo studies have evaluated the effects of interactions between host genetic and acquired factors or gene × environment interactions (G × E) on AgNP toxicity in the respiratory system. The primary goal of this article is to review host genetic and acquired factors identified across in vitro and in vivo studies and prioritize those necessary for defining exposure limits to protect all populations. The impact of these exposures and the work being done to address the current limited protections are also discussed. Future research on G × E effects on AgNP toxicity is warranted and will assist with informing regulatory or recommended exposure limits that enforce special protections for all populations to AgNP exposures in occupational settings.