Since its discovery in 1998, the orexin system, composed of two G-protein coupled receptors, orexins 1 and 2, and two neuropeptide agonists, orexins A and B, has captured the attention of the scientific community as a potential therapeutic target for the treatment of obesity, anxiety, and sleep/wake disorders. Genetic evidence in rodents, dogs, and humans was revealed between 1999 and 2000, demonstrating a causal link between dysfunction or deletion of the orexin system and narcolepsy, a disorder characterized by hypersomnolence during normal wakefulness. These findings encouraged efforts to discover agonists to treat narcolepsy and, alternatively, antagonists to treat insomnia. This perspective will focus on the discovery and development of structurally diverse orexin antagonists suitable for preclinical pharmacology studies and human clinical trials. The work described herein culminated in the 2014 FDA approval of suvorexant as a first-in-class dual orexin receptor antagonist for the treatment of insomnia.