Existing treatments for major depressive disorder (MDD) usually take weeks to months to achieve their antidepressant effects, and a significant number of patients do not have adequate improvement even after months of treatment. In addition, increased risk of suicide attempts is a major public health concern during the first month of standard antidepressant therapy. Thus, improved therapeutics that can exert their antidepressant effects within hours or a few days of their administration are urgently needed, as is a better understanding of the presumed mechanisms associated with these rapid antidepressant effects. In this context, the N-methyl-D-aspartate (NMDA) antagonist ketamine has consistently shown antidepressant effects within a few hours of its administration. This makes it a valuable research tool to identify biomarkers of response in order to develop the next generation of fast-acting antidepressants. In this review, we describe clinical, electrophysiological, biochemical, and imaging correlates as relevant targets in the study of the antidepressant response associated with ketamine, and their implications for the development of novel, fast-acting antidepressants. We also review evidence that alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) to NMDA throughput may represent a convergent mechanism for the rapid antidepressant actions of ketamine. Overall, understanding the molecular basis of this work will likely lead to the ultimate development of improved therapeutics for MDD.