Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamus-pituitary-adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Accordingly, reduced GR function has also been demonstrated in vitro, in peripheral tissues of depressed patients, as shown by reduced sensitivity to the effects of glucocorticoids on immune and metabolic functions. We and others have shown that antidepressants in vitro are able to modulate GR mRNA expression, GR protein level and GR function. This paper reviews the in vitro studies that have examined the effect of antidepressants on GR expression, number and function in human and animal cell lines, and the possible molecular mechanisms underlying these effects. Antidepressants are shown to both increase and decrease GR function in vitro, based on different experimental conditions. Specifically, increased GR function is likely to be mediated by an increased intracellular concentration of glucocorticoids, while decreased GR function seems to be the consequence of GR downregulation. We suggest that the study of the effects of antidepressants on glucocorticoid function might help clarify the therapeutic action of these drugs.