There has been significant interest in defining mechanisms of microbiome-immune system crosstalk and its influence on therapy. We have identified a key role for tryptophan-derived microbial metabolites in induction of an immune-suppressive program in tissue-resident macrophages that attenuates T cell function promoting tumor growth. In this seminar I will describe mechanisms that are essential for microbiome-innate immune crosstalk, potential avenues of therapeutic intervention in this regulatory circuit, as well as recent developments in the field that reveal the challenging complexity of bacterial tryptophan metabolization, disease pathology, and the response to a variety of therapeutic modalities.