Clinical evidence is accumulating to support the use of ketamine as a powerful, quick-acting intervention for depression. Ketamine has been administered by oral, sublingual, transmucosal, intravenous, intramuscular, subcutaneous, intranasal, and even rectal routes. Whereas intravenous ketamine is the best studied approach, common sense dictates that oral ketamine is the most practical. The bioavailability of oral ketamine and interindividual variations thereof have been poorly studied; possibly only 20%-25% of an oral dose reaches the bloodstream. This is not necessarily a limitation because, as with other drugs that have poor oral bioavailability, compensation is possible by administering an appropriately higher dose, and interindividual variations can be addressed through individualized dose up-titration. A quarter- century of experience supports the use of oral ketamine for treating acute and chronic pain in children and adults. Case reports, case series, chart reviews, and 3 recent randomized controlled trials (RCTs) show that oral ketamine is effective in treating severe depression, depression with suicidal ideation, and treatment-resistant depression; that oral ketamine, used as an augmentation agent, improves outcomes in patients receiving a conventional antidepressant; and that oral ketamine reduces depression in patients with chronic pain. Doses of oral ketamine have ranged from 0.25 to 7 mg/kg and from 50 mg per occasion to 300 mg per occasion in multiple daily dosing, daily dosing, and intermittent dosing schedules. Oral ketamine was well tolerated in all studies; dropout and reasons for dropout were similar in ketamine and control arms in the 3 RCTs. These findings suggest that if ketamine is to find a place as an off-label treatment for depression and suicidality in mainstream psychiatry, researchers should study the safety, efficacy, and optimization of oral ketamine. Intravenous and intranasal routes may be monetarily more promising, but the oral route could be of greatest service.