© 2019 Elsevier Ltd The human body harbors trillions of commensal microbes which play a crucial role in host development of the immune system, gastrointestinal tract, and brain. An alteration in the composition or function of these microbes has been implicated in numerous neurological, neuropsychological, and gastrointestinal diseases. The germ-free rodent model, devoid of all microbes, has been increasingly used to uncover the microbial underpinnings of these diseases and to investigate potential therapeutic treatment options. This review describes the utility and limitations of this approach to assess microbiota-gut-brain axis. In particular we emphasize key differences in gross anatomy, neuroimmunity, the enteric nervous system, the blood brain barrier, gene expression, neurogenesis, myelination and behavior in the germ-free rodent model. Taken together, despite the lack of direct translational relevance the germ-free rodent has been a very useful tool to bolster knowledge of how microbes modulate brain and behavior.