The gut microbiota provide crucial functions to their host, impacting diverse aspects of biology from metabolism and immunity to behavior. Thus, shifts in the microbiota can be an important pathway by which animals respond to environmental change. Some microbial shifts can benefit the host, but others are likely to be costly. Domestication is an evolutionary process which resulted in substantial genetic and ecological changes with potentially profound implications for the microbiota. The domestic microbiota are predicted to resemble that of modern industrialized human populations as the disruptions to historic host-microbe relationships were similar—including diet shifts, changes in movement and density, antibiotic use, and altered breeding and birthing. Microbial changes may not have been exclusively negative, however, and microbial responses to domestication that enhanced host phenotypes valuable to humans may even have been selected for. Drawing on comparative observational datasets and experiments in wild and domestic mice and canids, I have found that the domestic microbiota shows enhanced metabolism for domestic diets but may have lost traits relevant to host immunity. Beyond illuminating the role of the microbiota in domestic animal evolution, these data have potential application in promoting health as domestic animals are the primary organisms for biomedical research and are important sources of zoonotic diseases.