TAK-994 is an oral, selective OX2R agonist developed by Takeda for the treatment of narcolepsy type 1 (with cataplexy) and type 2 (without cataplexy). The molecule follows Takeda’s previous clinical molecule, TAK-925 (danavorexton), which was the first OX2R agonist to be tested in people with NT1 but had poor oral bioavailability and was administered intravenously in the clinic. With pioneering human proof-of-concept data from TAK-925, Takeda and other companies shifted focus to oral molecules like TAK-925. Despite remarkable clinical efficacy in a Ph. II trial, recently reported in NEJM, promising preclinical results that were disclosed this month, and a Breakthrough Therapy Designation, TAK-994 Ph. II trials for treatment of NT1 and NT2 were discontinued due to reported liver toxicity concerns. This article reviews the chemistry and pharmacology of TAK-994, and discusses what’s next in orexin agonism.