Barrier surfaces throughout the body are colonized with distinct communities of microbes. Composing the microbiota, these microbes have emerged as important determinants of health and disease. Indeed, these commensal microbes can impact disease pathogenesis in a compartmentalized manner, in the case of the skin microbiota in atopic dermatitis and the gut microbiota in colorectal cancer. In addition to these well described local effects, gut microbes have been demonstrated to influence systemic immune responses via the production and secretion of metabolites. Notably, recent studies suggest this systemic immune activation by the microbiome extends to the efficacy of checkpoint inhibitor immunotherapy; in other words, selected bacterial species may confer greater likelihood of treatment responsiveness in non-gastrointestinal cancers. Following these recent observations, we and others are conducting longitudinal stool collections in a number of Cancer Immunotherapy clinical trials. With such collections, it will be possible to evaluate how baseline or on treatment microbiota signatures correlate with outcome across indications and treatment combinations. To complement microbiome studies in these and other patient populations, analysis of samples from healthy volunteers is necessary to understand how gut microbes impact systemic immune responses in the steady state.