Actelion Pharmaceuticals achieved clinical proof-of-concept for the treatment of insomnia in 2007 with the release of Phase II data on Almorexant, a potent dual (OX1R/OX2R) orexin receptor antagonist. GlaxoSmithKline also released clinical efficacy data on an orexin receptor antagonist in 2007 for the treatment of insomnia. With these exciting findings, the search for orexin (or hypocretin) receptor antagonists for the treatment of sleep and neurological disorders has recently increased in intensity in the pharmaceutical industry. This review will focus on the medicinal chemistry of orexin antagonists and the potential therapeutic value of this therapy for the treatment of insomnia. Receptor subtype selectivity will also be described to highlight the tools currently available to delineate receptor-specific pharmacology.