Significance Stress-related disorders are prevalent worldwide, but the pathophysiology of these disorders and specific therapeutic targets remain elusive. Two hypothetical frameworks show great promise: decreased neurotrophic support and decreased responsiveness to glucocorticoids. Our study shows that the glucocorticoid receptor is a prominent target of the brain-derived neurotrophic factor (BDNF) signaling, which gives rise to unique functional attributes essential for the neuroplasticity to an antidepressant. We propose a unifying mechanism of BDNF-priming of glucocorticoid signaling, which provides new prospects for discovering innovative treatments for disorders featuring unpaired BDNF and glucocorticoid activities. Eliciting glucocorticoid receptor phosphorylation is an attractive means to confront resistance to antidepressants.