Orexin (hypocretin) neuropeptides exert multiple biological functions via activation of two G protein-coupled receptors, orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). Loss of orexin neurons is associated with narcolepsy type 1 (NT1); therefore, targeting the orexin system may be an effective therapeutic approach for NT1. Development of small-molecule orexin receptor agonists requires consideration of the following challenges: (1) blood-brain barrier permeability, (2) identification of the appropriate target receptor (OX1R and/or OX2R) to be activated, (3) long-term functional integrity of orexin receptors after long-term loss of orexin in NT1, and (4) potential for stimulation of orexin release as a result of OX2R activation. The recent discovery and characterization of a parenteral OX2R agonist danavorexton (TAK-925) and oral TAK-994 have resulted in scientific breakthroughs to answer these questions. This chapter provides an overview of recent progress in the characterization of OX2R agonists as medicines for NT1.