Narcolepsy is a chronic, debilitating neurological disorder of sleep-wake state instability. This instability underlies all narcolepsy symptoms, including excessive daytime sleepiness (EDS), symptoms of rapid eye movement (REM) sleep dysregulation (ie, cataplexy, hypnagogic/hypnopompic hallucinations, sleep paralysis), and disrupted nighttime sleep. Several neurotransmitter systems promote wakefulness, and various neural pathways are involved in regulating REM sleep-related muscle atonia, providing multiple targets for pharmacologic intervention to reduce EDS and cataplexy. Medications approved by the US Food and Drug Administration (FDA) for the treatment of EDS in narcolepsy include traditional stimulants (eg, amphetamines, methylphenidate), wake-promoting agents (eg, modafinil, armodafinil), and solriamfetol, which mainly act on dopaminergic and noradrenergic pathways. Sodium oxybate (thought to act via GABA_B receptors) is FDA-approved for the treatment of EDS and cataplexy. Pitolisant, a histamine 3 (H₃)-receptor antagonist/inverse agonist, is approved by the European Medicines Agency (EMA) for the treatment of narcolepsy with or without cataplexy in adults and by the FDA for the treatment of EDS in adults with narcolepsy. Pitolisant increases the synthesis and release of histamine in the brain and modulates the release of other neurotransmitters (eg, norepinephrine, dopamine). Antidepressants that inhibit reuptake of serotonin and/or norepinephrine are widely used off label to manage cataplexy. In many patients with narcolepsy, combination treatment with medications that act via different neural pathways is necessary for optimal symptom management. Mechanism of action, pharmacokinetics, and abuse potential are important considerations in treatment selection and subsequent medication adjustments to maximize efficacy and mitigate adverse effects in the treatment of patients with narcolepsy.