The response and adaptation of the pituitary-adrenal system to chronic stresses was investigated. These included individual caging, confinement, and exposure to cold for varying periods of time. Studies were carried out demonstrating that during the period of adaptation when plasma corticosterone concentrations returned toward their prestress level despite continued exposure to the stressor, the animals responded to additional stimuli of ether for 1 min, a saline injection, or release from confinement with a faster increase (within 2.5 min) in plasma corticosterone than controls (10 min). This increased responsiveness was not limited to the adrenal since plasma ACTH showed a greater increase 2.5 min after ether in animals confined for 40 min than in nonconfined rats. It is concluded that during adaptation to a chronic stress the pituitary-adrenal system is not inhibited by the circulating steroid level but is actually hypersensitive to additional stimuli. Thus, chronic stress may cause an increased drive to the ACTH-secreting mechanism which compensates or overrides the cortical feedback.