Ambient air pollution clearly associates with adverse health effects and is a top 10 contributor to the global disease burden. Despite efforts to regulate these exposures, adverse health effects remain. Therefore, in parallel with mitigation efforts, we need to focus on understanding the factors that drive an individual's susceptibility to air pollution. Conceptually, these are defined as gene-by-environment interactions. In this framework, an individual's genetic composition influences his or her response to exposures in the environment. However, we are increasingly aware that nongenetic host factors, such as age, obesity, diabetes mellitus, and diet, influence air pollution responses. The interactions between these factors are just beginning to be unraveled. For example, recent literature has identified that ozone pulmonary responses have sex-specific effects. Work in several laboratories has shown that male and female mice exhibit different 03-induced airway hyperresponsiveness (AHR) and that these effects are related to sex hormones or sex-dependent effects on the microbiome. Although modification of sex hormones represents an interesting experimental target, as a target strategy to reduce O3 health effects it may have limited appeal. Alternatively, the microbiome can be modified by diet, and therefore dietary modifications might be a viable strategy.