Our immune system is charged with the vital mission of identifying invading pathogens and mounting proper inflammatory responses. During the process of clearing infections, the immune system often causes considerable tissue damage. Conversely, if the target of immunity is a member of the resident microbiota, uncontrolled inflammation may lead to host pathology in the absence of infectious agents. Recent evidence suggests that several inflammatory disorders may be caused by specific bacterial species found in most healthy hosts. Although the mechanisms that mediate pathology remain largely unclear, it appears that genetic defects and/or environmental factors may predispose mammals to immune-mediated diseases triggered by potentially pathogenic symbionts of the microbiota. We have termed this class of microbes ‘pathobionts’, to distinguish them from acquired infectious agents. Herein, we explore burgeoning hypotheses that the combination of an immunocompromised state with colonization by pathobionts together comprise a risk factor for certain inflammatory disorders and gastrointestinal (GI) cancer.