The microbiome of the built environment (MoBE) is a relatively new area of study. While some knowledge has been gained regarding impacts of the MoBE on the human microbiome and disease vulnerability, there is little knowledge of the impacts of the MoBE on mental health. Depending on the specific microbial species involved, the transfer of microorganisms from the built environment to occupant's cutaneous or mucosal membranes has the potential to increase or disrupt immunoregulation and/or exaggerate or suppress inflammation. Preclinical evidence highlighting the influence of the microbiota on systemic inflammation supports the assertion that microorganisms, including those originating from the built environment, have the potential to either increase or decrease the risk of inflammation-induced psychiatric conditions and their symptom severity. With advanced understanding of both the ecology of the built environment, and its influence on the human microbiome, it may be possible to develop bioinformed strategies for management of the built environment to promote mental health. Here we present a brief summary of microbiome research in both areas and highlight two interdependencies including the following: (1) effects of the MoBE on the human microbiome and (2) potential opportunities for manipulation of the MoBE in order to improve mental health. In addition, we propose future research directions including strategies for assessment of changes in the microbiome of common areas of built environments shared by multiple human occupants, and associated cohort-level changes in the mental health of those who spend time in the buildings. Overall, our understanding of the fields of both the MoBE and influence of host-associated microorganisms on mental health are advancing at a rapid pace and, if linked, could offer considerable benefit to health and wellness.