Under normal, unstressed conditions, the body maintains a dynamic equilibrium known as homeostasis--a complex interplay balancing the conflicting demands presented by many internal and external forces. In the face of threatened or actual disruptions (i.e., stress), molecular, cellular, physiologic, and behavioral responses act to restore homeostasis. These responses can be specific to a particular stressor and relatively circumscribed (e.g., secretion of insulin in response to an increase in blood glucose), or can be generalized and relatively nonspecific (e.g., behavioral manifestations of severe anxiety). Typically, more nonspecific and generalized responses occur in the setting of severe and threatening disruptions in homeostasis, and taken together, these responses are known as the "general adaptation or stress syndrome". We will describe the elements and organization of the generalized stress response with particular attention to the hypothalamic-pituitary-adrenal axis as it interacts with the immune system, and we will review what is known about this interactive network in the setting of critical illness.