This chapter deals with the role of ketamine in treatment-resistant depression (TRD). Ketamine is a noncompetitive N-methyl-D-aspartate (NMDA) antagonist. Ketamine has also been reported to exert cholinergic effects, inhibiting nicotinic ACh receptor activation, while also raising ACh levels by inhibiting acetylcholinesterase. Ketamine has a chiral center at the C-2 carbon of the cyclohexanone ring, resulting in two enantiomers. Ketamine administration may include intravenous (IV), intramuscular (IM), intranasal (IN), intrarectal, epidural, subcutaneous, transdermal, intra-articular, sub-lingual, and oral routes. Repeated-dose protocols are commonly used for electroconvulsive therapy (ECT) in TRD, and ketamine has been repeatedly dosed in chronic pain conditions. The Montgomery-Asberg Depression Rating Scale (MADRS) suicide item (MADRSSI) and Beck Scale for Suicidal Ideation (SSI) were used to assess explicit suicidal ideation. Much of the available information on chronic ketamine use involves small groups of poly-drug-abusing subjects.