In recent years, dysfunction of hypothalamic-pituitary-adrenal (HPA) axis function has been implicated in a wide variety of psychiatric conditions. The importance of this system in responding to and coping with stress is well documented, and the integrity of such systems is of obvious significance to good mental health. The prefrontal cortex (PFC) is also heavily implicated in numerous psychopathological conditions. There is thus a growing interest in the potential role the PFC might play in regulating HPA function, and whether abnormalities of these systems are linked. The present paper reviews a number of recent animal studies which have attempted to elucidate the role of the PFC in regulation of HPA axis function, and how these systems may interact. It is concluded that the PFC is involved both in activating HPA responses to stress and in the negative feedback regulation of this system. Cerebral laterality is an important feature of this regulation, with the right PFC being most directly linked to stress-regulatory systems. On this basis, a number of parallels are drawn to the human literature, where asymmetrical disturbances in PFC activity may help explain associated patterns of HPA dysfunction.