Segmented filamentous bacteria (SFB) are commensal bacteria that were first identified in the ilea of mice and rats. Morphologically similar bacteria occur in a broad range of host species, but all strains have been refractory to in vitro culture thus far. Although SFB were once considered innocuous members of the intestinal microbiota of laboratory rodents, they are now known to affect the development of the immune system in rodents and, subsequently, the phenotype of models of both enteric and extraintestinal disease. Therefore, SFB represent long-recognized commensal bacteria serving as an intercurrent variable in studies using rodent models of disease. Here we describe the basic biology of SFB and discuss the immunologic and physiologic effects of colonization with SFB, with particular attention to their effects on rodent models of disease. In addition, we propose that SFB represent only the 'tip of the iceberg' in our understanding of the influence of the microbiota on model phenotypes. As next-generation sequencing techniques are increasingly used to investigate organisms that are refractory to culture, we are likely to identify other commensal microbes that alter the models we use. This review underscores the need to characterize such host-microbe interactions, given that animal research represents a critical tool that is particularly vulnerable to scrutiny in an era of decreasing financial resources and increasing accountability for the use of animal models.