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Exposure to stressful life events is associated with a high risk of developing psychiatric disorders with a wide variety of symptoms. Cognitive symptoms in stress-related psychiatric disorders can be particularly challenging to understand, both for those experiencing them and for healthcare providers. To gain insights, it is important to capture stress-induced structural, epigenomic, transcriptomic, and proteomic changes in relevant brain regions such as the amygdala, hippocampus, locus coeruleus and prefrontal cortex, resulting in long-lasting alterations in brain function. In this review, we will emphasize a subset of stress molecular mechanisms altering neuroplasticity, neurogenesis, and balance between excitatory and inhibitory neurons. We then discuss how to identify genetic risk factors that may accelerate stress-driven or stress-induced cognitive impairment. Despite the development of new technologies such as single-cell resolution sequencing, our understanding of the molecular effects of stress in the brain remains to be deepened. A better understanding of the diversity of stress effects in different brain regions and cell types is a pre-requisite to open new avenues for mechanism-informed prevention and treatment of stress-related cognitive symptoms.