<p>Motion sickness is a nearly universal response to the unnatural motions that are experienced when traveling by means other than the body’s own faculties; in artificial realities; and in micro- and partial gravity environments. Despite being a known malady since ancient times, its underlying mechanisms, as well as the marked interpersonal variability in susceptibility, remain incompletely understood. While efferent brain-to-body signaling pathways involved in motion sickness have been previously described, recent findings on the functional role of the gut’s (neuro)epithelial cells and microbiome point to a more intricate biological control system than previously appreciated. We examine (afferent) anatomical, hormonal, immune, and extracellular brain-body pathways, and their potential role in motion sickness etiology. This perspective proposes that an additional route may contribute to the pathophysiology of motion sickness, potentially under regulatory influence of the enteric nervous system. Candidate initiators, acting on these pathways, include humoral agents, enteroendocrine cells, and the gut microbiome.</p>