Stress encompasses the psychological perception of pressure from the environment, and the body’s physiological response to it. The sources of stress have evolved over time, from predation and natural disasters, to things like interpersonal conflicts and economic insecurities. While in the past, stressors evoked a very acute physical ‘fight or flight’ response, these events are rare in today’s terms. In contrast, the stressors we experience in the modern world are arguably more trivial – they are not often immediately life threatening – however they are more persistent, manifesting as a chronic, low level source of anxiety in our daily lives. The natural stress response involves multiple systems and is designed to provide short-term beneficial effects to the individual to help see them through a threatening situation. It is thought this response is mediated largely through glucocorticoid (GC) production and will rapidly normalize following the stressful event. In the event of chronic exposure to stress, some of these short-term physiological changes fail to return to ‘normality’, and as a result, the nature of our homeostasis is altered. This chapter will focus on the changes to the immune system and brain mediated through exposure to stress, with particular emphasis on the detrimental effects of chronic stress.