Stress-related disorders represent one of the major health-care burdens in modern society. The neuroendocrine stress response is coordinated through the dynamic interplay between the brain and the endocrine regulation of the anterior pituitary and adrenal glands - the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is a classic example of homeostatic feed-forward and feedback loops working together to control system output and function. Central to the control of the HPA axis is the coordinated activity of ion channels and cellular electrical excitability in the key nodes of the axis - hypothalamic neurones, anterior pituitary corticotrophs and adrenal cortical cells. However, while the inputs and outputs of each node are well understood how the electrical properties of these systems is controlled and whether disturbances in ion channel properties may underlie disease states associated with HPA axis dysfunction is very poorly understood. This talk is aimed at identifying some of the major challenges in understanding HPA axis function from both a physiological and modelling viewpoint and to stimulate new research avenues that should lead to improved predictive tools to understand HPA axis function in health and disease. Preliminary work exploiting an integrated approach to understand the complex interplay between multiple ion channels and their control of distinct nodes of the HPA axis will be discussed.