Urbanization has led to systemic environmental factors that degrade air quality and microbial diversity, negatively impacting human health and wellbeing. Conventional building Heating, Ventilation and Air Conditioning (HVAC) units that filter airborne pollutants and support Indoor Air Quality (IAQ), are often energy intensive, decrease indoor microbial diversity, and are still unable to address specific pollutants or seasonal psychrometric profiles. Although HVAC performance, IAQ, and human health have long been correlated, emerging fields of study such as metagenomics may enable more inclusive metrics in the characterization of these co-relationships. As part of a rapidly expanding field of research, metagenomic analyses of human and indoor microbiomes have begun to demonstrate how patterns of urban development can impact microbial diversity and interrelated human health indicators, many of which are similar to health impacts associated with urban air pollutants, such as immune health and response. However, measures of microbial ecology have yet to be systematically included in the characterization of IAQ. A review of literature including both air quality and microbiome metrics reveals significant interrelated factors and impacts on human health and wellbeing, implying potentially confounding/compounding variables. While many design decisions impact indoor microbiomes, some do so with potentially larger impacts, such as building-integrated plant-based systems, which may significantly affect indoor microbial ecologies in unexplored ways. However, assessing their impact on urban health and wellbeing, building energy use, and outdoor and indoor air quality requires more systematic integration of emerging knowledge in the fields of both air quality and metagenomics. Further, the integration of measures of microbial metabolism and metagenomic analyses could enable more precise and specific evaluations of the potential for pollutant degrading processes in the design of urban green infrastructure and Indoor Environmental Quality (IEQ), such as the incorporation of bioremediation processes into urban air treatment programs.