While the idea that the gut and brain communicate has been appreciated for centuries and commented on in many literary works, the formal introduction of the term "gut-brain axis" was much more recent. To the lay person, the operations of this axis are best represented by the effects of stress on gastrointestinal function. Indeed, exactly how stress impacts on such functions as motility and secretion has been extensively studied and its modus operandi revealed. Brain-to-gut communications can be effected via the autonomic nervous system or the hypothalamic pituitary adrenal axis. The recognition that the vagus nerve is predominantly comprised of sensory neurons led to the realization that gut-to-brain traffic is ubiquitous and largely subconscious only achieving conscious recognition at times of alarm or when the gut is injured or diseased. As the field of neurogastroenterology has developed, our understanding of the parallel involvement of "big" and "little" brains by neurodegenerative diseases has increased with Parkinson disease being the exemplar. Of late, the microbiome has entered the fray, and the concept of the microbiome-gut-brain axis emerged. Animal studies have provided considerable evidence to indicate that the gut microbiome can influence brain morphology and function and, thereby, modify behavior. Studies in animal models have also revealed that signals from on high can alter microbiome composition and function. For understandable reasons, it has proven more challenging to explore the microbiota-gut-brain axis and its implications to health and disease in humans. Nevertheless, the possibility that microbiome modulation could exert positive impacts on neurologic and psychological disorders has attracted considerable interest and some hints of efficacy have begun to emerge. For now, pending further studies in humans caution needs to be exerted in assigning pathogenic significance to interactions between the gut microbiome and the brain.