Glucocorticoids acting through the type II glucocorticoid receptor (GR) are critical for maintenance of homeostasis after both psychological and physiological stress. This notion is exemplified by impaired survival of humans with adrenal insufficiency, the association of dysregulation of the hypothalamic-pituitary-adrenal axis with psychiatric disorders, and the bidirectional interplay of the adrenal axis with the immune system. To understand the essential actions of glucocorticoids acting through GR to maintain homeostasis, identification of key cell and gene targets is needed. In this regard, genetic model systems to define mechanisms of GR actions at the cellular and genomic levels have proven informative. Global deletion of GR results in neonatal lethality and dramatic glucocorticoid overproduction, a phenotype that precludes analysis of GR function in later development and that may confound interpretation by grossly elevated glucocorticoid concentrations exerting effects on other nuclear receptor types. To minimize these limitations, we have utilized the Cre recombinase – loxP system to delete GR specifically in the forebrain, T cells, and the macrophage/neutrophil lineage. Mice with forebrain-restricted deletion of GR (FBGRKO) demonstrate heightened adrenal axis activity, despair-like behaviours responsive to anti-depressants, and aberrant locomotor activation in association with stress. Given the adult onset of deletion of GR in FBGRKO mice and the temporal relationship of GR deletion to behavioural abnormalities, these effects are not likely due to developmental aspects of GR function but rather to changes in glucocorticoid responsiveness in the adult. Mice with deletion of GR in T cells (TGRKO) or macrophages (MGRKO) demonstrate augmented cytokine production and increased lethality with immune system activation. Cyclooxygenase (COX)-2 proved to be a critical target for GR actions as COX-2 inhibitors rescued each line from lethality after immune activation. Our recent studies in MGRKO mice have identified GR modulation of p38 MAPK activity as a key target for GR anti-inflammatory actions after toll-like receptor 4 engagement, while ERK, Akt, and JNK were not glucocorticorticoid responsive. Our ongoing studies will attempt to more rigorously restrict GR deletion to specific brain and body sites utilizing a lentivirus-Cre delivery system to facilitate later gene profiling efforts.