Pharmacological and anatomical evidence suggests that abnormal glutamatergic neurotransmission may be associated with the pathophysiology of depression. Compounds that act as NMDA receptor antagonists may be a potential treatment for depression, notably the rapid-acting agent ketamine. The rapid-acting and sustained antidepressant effects of ketamine rely on the activation of AMPA receptors (AMPARs). As the key elements of fast excitatory neurotransmission in the brain, AMPARs are crucially involved in synaptic plasticity and memory. Recent efforts have been directed toward investigating the bidirectional dysregulation of AMPAR-mediated synaptic transmission in depression. Here, we summarize the published evidence relevant to the dysfunction of AMPAR in stress conditions and review the recent progress toward the understanding of the involvement of AMPAR trafficking in the pathophysiology of depression, focusing on the roles of AMPAR auxiliary subunits, key AMPAR-interacting proteins, and posttranslational regulation of AMPARs. We also discuss new prospects for the development of improved therapeutics for depression.© 2022 The Authors.