Antidepressants that produce rapid and robust effects, particularly for severely ill patients, represent one of the largest unmet medical needs for the treatment of depression. Currently available drugs that modulate monoamine neurotransmission provide relief for only a subset of patients, and this minimal efficacy requires several weeks of chronic treatment. The recent discovery that the glutamatergic agent ketamine produces rapid antidepressant responses within hours has opened a new area of research to explore the molecular mechanisms through which ketamine produces these surprising responses. Clinical and preclinical findings have exposed some of the unique actions of ketamine and identified a cell-signaling pathway known as the mammalian target of rapamycin. Activation of mammalian target of rapamycin and increased synaptogenesis in the prefrontal cortex are crucial in mediating the antidepressant effects of ketamine. Importantly, the synaptic actions of ketamine allow rapid recovery from the insults produced by exposure to repeated stress that cause neuronal atrophy and loss of synaptic connections. In the following review, we explore some of the clinical and preclinical findings that have thrust ketamine to the forefront of rapid antidepressant research and unveiled some of its unique molecular and cellular actions.