In Japan, there is a traditional proverb: “Illness begins in the mind.” Indeed, it is a common experiential understanding that one’s mental state can influence physical health. For instance, stress is known to trigger or exacerbate irritable bowel syndrome (IBS). While the concept that “illness begins in the mind” is widely recognized, the underlying mechanisms remain largely unexplored. In the present chapter, possible mechanisms are shown to clarify the concept. Knowledge regarding the relationship between the central nervous system (CNS) and gastrointestinal functions such as gastrointestinal motility, visceral sensation, and intestinal barrier function is increasing. For over 35 years, our research group has consistently investigated CNS regulation of gastrointestinal function. For instance, neuropeptide orexin acts centrally in the brain to improve gastrointestinal motility, visceral sensation, and intestinal barrier function. In turn, decrease in orexin signaling in the brain may induce gastrointestinal dysmotility, visceral hypersensitivity, and leaky gut. These features are characteristic of the clinical presentation of IBS. Thus, impaired orexin function may provide a unifying explanation for the multifaceted pathophysiology of IBS. In this context, IBS (“illness”) may arise from reduced central orexin signaling (“mind”), supporting the concept that “illness begins in the mind.”