The discovery of ketamine's rapid antidepressant action has generated intense interest in the field of neuropsychiatry. This discovery demonstrated that to alleviate the symptoms of depression, treatments do not need to elicit substantive alterations in neuronal circuitry or trigger neurogenesis, but rather drive synaptic plasticity mechanisms to compensate for the underlying pathophysiology. The possibility of a rapidly induced antidepressant effect makes therapeutic pursuit of fast-acting neuropsychiatric medications against mood disorders plausible. In the meantime, the accumulating clinical as well as preclinical observations raise critical questions on the nature of the specific synaptic plasticity events that mediate these rapid antidepressant effects. This work has triggered the current growing interest in alternative psychoactive compounds that are thought to have similar properties to ketamine and its action. This review covers our insight into these questions based on the work our group has conducted on this topic in the last decade.