Abstract Advances in understanding the neurochemistry of sleep and waking have stimulated new pharmacological directions in the treatment of insomnia. While the sedation of historic insomnia medications was discovered serendipitously, now compounds can be developed for specific molecular targets with known sleep-related actions. Numerous investigational compounds, including some entirely novel approaches, are being evaluated currently as possible insomnia treatments. In recent years the US Federal Drug Administration (FDA) has approved medications with new pharmacodynamic and pharmacokinetic properties thereby extending the options for personalized pharmacotherapy. The FDA is reviewing new applications for innovative sleep-promoting medications currently, including suvorexant and tasimelteon. Presently the FDA-approved insomnia treatment medications include benzodiazepine receptor agonists available in immediate-release, extended-release, and alternative delivery oral absorption formulations; a melatonin receptor agonist; and a histamine receptor antagonist. Clinical indications include insomnia associated with difficulty with sleep onset, sleep maintenance, and middle-of-the-night awakenings. Alternative approaches to treating insomnia have included prescription medications employed on an off-label basis for insomnia, over-the-counter sleep aids, and assorted unregulated substances marketed to enhance sleep.