We have reviewed two areas of research on stress, memory, and synaptic plasticity which may be relevant toward understanding the neurobiology of major depressive disorder (MDD). First, we have presented the view that the hippocampus (HC) and prefrontal cortex (PFC) function jointly as a memory system which enables multitask processing (working memory) and consolidation of contextual information. The amygdala, by contrast, is necessary for the consolidation of emotional memories. Cognitive and neurophysiological studies have shown that HC-PFC processing is impaired, and amygdaloid processing is enhanced, by stress and in anxiety and mood disorders, including MDD. Second, we have reviewed research on the behavioral and neurophysiological actions of tianeptine, an antidepressant that is known to block the adverse effects of chronic stress on hippocampal morphology. Recent work has shown that acute tianeptine enhances cognitive and electrophysiological measures of HC-PFC functioning without interfering with the emotion-induced enhancement of amygdaloid functioning in rodents. We conclude with a synthesis of the preclinical and clinical literature on stress, memory, and tianeptine with the proposal that tianeptine should enhance HC-PFC memory-related processing in people under stress.