Major Depressive Disorder (MDD) is a leading cause of disability worldwide. Conventional antidepressant treatment is characterised by a significant time to onset of therapeutic action (approximately 2 weeks) and fails to achieve a stable remission of symptoms in one-third of subjects with MDD. In the last 20 years the discovery of antidepressant effects of the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine as a rapid acting (within hours) and sustained (up to 7 days) antidepressant has represented a major paradigm shift in the field.The present chapter reviews the pharmacology, safety, and efficacy of ketamine as a novel therapeutic agent for MDD and specifically for subjects who did not respond to conventional antidepressant (treatment resistant depression). The impact of ketamine on suicidal ideation, the availability of brain biomarkers of ketamine treatment response and the association of ketamine and psychotherapy are considered.