Commensal microbes form distinct ecosystems within their mammalian hosts, collectively termed microbiomes. These indigenous microbial communities broadly expand the genomic and functional repertoire of their host and contribute to the formation of a “meta-organism.” Importantly, microbiomes exert numerous biochemical reactions synthesizing or modifying multiple bioactive small molecules termed metabolites, which impact their host's physiology in a variety of contexts. Identifying and understanding molecular mechanisms of metabolite–host interactions, and how their disrupted signaling can contribute to diseases, may enable their therapeutic application, a modality termed “postbiotic” therapy. In this review, we highlight key examples of effects of bioactive microbe-associated metabolites on local, systemic, and immune environments, and discuss how these may impact mammalian physiology and associated disorders. We outline the challenges and perspectives in understanding the potential activity and function of this plethora of microbially associated small molecules as well as possibilities to harness them toward the promotion of personalized precision therapeutic interventions.