Sleepiness is a common side-effect of drugs which act on the central nervous system. Drugs cause sedation via effects on the neural systems involved in sleep-wake regulation, primarily by increasing GABA or inhibiting histamine, norepinephrine, or serotonin. This chapter reviews drugs for which sleepiness is considered a side-effect. Drugs used as hypnotics include anxiolytic benzodiazepines, sedating antidepressants, antiepileptics, antihistamines, antipsychotics, barbiturates, sodium oxybate, and valerian. The principal drugs used to treat Parkinson's disease are levodopa/carbidopa and dopamine agonists. The neurobiology of pain is complex and involves both peripheral and central mechanisms. Multiple neurotransmitters modulate pain processing, including substance P, endorphins, norepinephrine, and serotonin. Alcohol-induced sleep disruption may decrease next-day alertness and performance. Important factors affecting degree of sedation include receptor binding profile, dose, half-life, and time of administration. The consequences of daytime sleepiness which include impaired performance and increased risk of accidents must be considered when prescribing medications.