In the era of mutant mice generated as molecular in vivo models for complex pathogenetic and therapeutic aspects of particular human diseases, glucocorticoid receptor transgenic mice represent an interesting and promising tool. Animals carrying mutations of this receptor show alterations in the hypothalamic-pituitary-adrenal (HPA)-system, which are comparable to those observed in depressed patients. Furthermore, similarities that may model the human disease have been described on the behavioral and pharmacological level, which increase the impact of such mutants. In this review we summarize different approaches used to alter or eliminate glucocorticoid receptor expression and function, and discuss their relevance as models for depression.