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The brain is one of the most metabolically active organs in the body. The brain’s high energy demand associated with wakefulness persists during rapid eye movement sleep, and even during non–rapid eye movement sleep, cerebral oxygen consumption is only reduced by 20%. The active bioenergetic state parallels metabolic waste production at a higher rate than in other organs, and the lack of lymphatic vasculature in brain parenchyma is therefore a conundrum. A common assumption has been that with a tight blood–brain barrier restricting solute and fluid movements, a lymphatic system is superfluous in the central nervous system. Cerebrospinal fluid (CSF) flow has long been thought to facilitate central nervous system tissue “detoxification” in place of lymphatics. Nonetheless, while CSF production and transport have been studied for decades, the exact processes involved in toxic waste clearance remain poorly understood. Over the past 5 years, emerging data have begun to shed new light on these processes in the form of the “glymphatic system,” a novel brain-wide perivascular transit passageway dedicated to CSF transport and metabolic waste drainage from the brain. Here, we review the key anatomical components and operational drivers of the brain’s glymphatic system, with a focus on its unique functional dependence on the state of arousal and anesthetic regimens. We also discuss evidence for why clinical exploration of this novel system may in the future provide valuable insight into new strategies for preventing delirium and cognitive dysfunction in perioperative and critical care settings.