Pitolisant (Wakix), an orally available, first-in-class antagonist/inverse agonist of the histamine 3 receptor, is approved in the EU (as of March 2016) for the treatment of narcolepsy with or without cataplexy in adults and in the USA (as of August 2019) for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy. Pitolisant was demonstrated to have minimal risk of abuse in preclinical and clinical studies, and is the only anti-narcoleptic drug not scheduled as a controlled substance in the USA. The totality of evidence from pivotal and supportive phase III trials suggests that pitolisant administered at up to the recommended maximum dose of 36 mg once daily reduces EDS and cataplexy in adults with narcolepsy relative to placebo. Noninferiority of pitolisant to modafinil in the management of EDS was not demonstrated. Pitolisant was generally well tolerated in clinical trials. Consistent with its mechanism of action, the most common treatment-emergent adverse events included headache, insomnia and anxiety. With minimal abuse potential and offering the convenience of oral, once-daily administration, pitolisant extends the range of approved treatment options available to adult patients with narcolepsy with or without cataplexy.