Ketamine has been used as a pharmacological model for schizophrenia as subanesthetic infusions have been shown to produce temporary schizophrenia-like symptoms in healthy humans. More recently, ketamine has emerged as a potential treatment for multiple psychiatric disorders, including treatment-resistant depression and suicidal ideation. However, the mechanisms underlying both the psychotomimetic and the therapeutic effects of ketamine remain poorly understood. This review provides an overview of what is known of the neural mechanisms underlying the effects of ketamine and details what functional MRI studies have yielded at a systems level focused on brain circuitry. Multiple analytic approaches show that ketamine exerts robust and consistent effects at the whole-brain level. These effects are highly conserved across human and nonhuman primates, validating the use of nonhuman primate models for further investigations with ketamine. Regional analysis of brain functional connectivity suggests that the therapeutic potential of ketamine may be derived from a strengthening of executive control circuitry, making it an intriguing candidate for the treatment of drug abuse. There are still important questions about the mechanism of action and the therapeutic potential of ketamine that can be addressed using appropriate functional neuroimaging techniques.