Tryptophan (Trp) metabolism plays a central role in sleep, mood, and immune system regulation. The kynurenine pathway (KP), which is regulated by the enzymes tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3 dioxygenase (IDO), which catalyze the conversion of Trp to kynurenine (Kyn), facilitates immune regulation and influences neurocognition. Notably, Kyn metabolites bind the N-methyl-d-aspartate receptor (NMDAR), essential for memory encoding, and in turn, cognition. Aberrant NMDAR activity through agonist binding influences excitability and cell death. In this issue of the JCI, Watne and authors demonstrate that KP pathway end products were elevated in the serum and the cerebrospinal fluid (CSF) of subjects with delirium. This observation provides insight regarding the basis of a variety of commonly observed clinical conditions including sundowning, abnormal sleep-wake cycles in hospitalized patients, neurodegenerative cognitive impairment, radiation-induced cognitive impairment, neurocognitive symptomatology related to COVID-19, and clinical outcomes observed in patients with CNS tumors, such as gliomas.