Exposure to chronic social stress is well recognised to precipitate and exacerbate psychiatric illness, most commonly major depression. While human imaging studies have provided many new insights into the neurobiological mechanisms involved in this association, animal models remain the only approach capable of providing information about cellular/sub-cellular events. At present, social defeat represents the gold-standard model for examining social stress in rats. In brief, this procedure involves an inexperienced male rat being defeated by a dominant male rat in a conflict setting. The defeat process is well recognised to generate a significant stress response (as characterised by HPA and sympathetic nervous system engagement) and produce profound changes in the defeated animal's mood and cognitive state. Research by our group and others has begun to reveal the specific neural circuitry and glial cell responses involved in responding to stress and driving the observed changes in CNS functions. Specifically, using delta-FosB detection to identify persistently activated neurons, and Iba-1 staining to identify activated microglia, we have discovered that the medial prefrontal cortex is a critical region for mediating the effects of chronic stress. We have also observed that the dynamic interaction between microglia and neurons in this region is significantly perturbed by stress exposure and may represent a useful first target for pharmacological manipulation. Progress has also been made in identifying the central neuromodulators involved in the regulation of social behaviour. Finally, our laboratory and others have begun to probe a variety of epigenetic alterations that may be responsible for the long term behavioural changes often observed following stress, including effects on the expression of stress-related peptides such as CRF. Thus far, we have identified that stress induces significant chromatin remodelling as well as profound changes in DNA methylation status. In this presentation I will review these important new developments and identify promising directions for future research.