Pain is one of the main symptoms that drives patients to seek physical therapy and its attenuation commonly defines a successful outcome. A large body of evidence is dedicated to elucidating the relationship between chronic stress and pain. A physiologic stress response may be triggered by fear or perceived threat to safety, status, or well-being, and elicits the secretion of sympathetic catecholamines (epinephrine and norepinepherine) and neuroendocrine hormones (cortisol) to promote survival and motivate success. Cortisol is a potent anti-inflammatory that functions to mobilize glucose reserves for energy and modulate inflammation. Cortisol may also facilitate the consolidation of fear-based memories for future survival and avoidance of danger. While short-term stress may be adaptive, maladaptive responses (such as magnification, rumination, or helplessness) to pain or non-pain-related stressors may increase the level of cortisol secretion and condition a sensitized physiologic stress response that is readily recruited. Ultimately, a prolonged or exaggerated stress response could perpetuate cortisol dysfunction, widespread inflammation, and pain. While stress may be unavoidable in life and challenges are inherent to success, humans have the capability to modify what they perceive as stressful and how they respond to it. Exaggerated psychological responses (eg: catastrophizing) following maladaptive cognitive appraisals of potential stressors as threatening may worsen cortisol secretion by facilitating fear-based activation of the amygdala. Coping, cognitive re-appraisal, or confrontation of stressors may minimize cortisol secretion and prevent chronic, recurrent pain. Given the parallel mechanisms underlying the physiologic effects of a maladaptive response to pain and non-pain-related stressors, physical therapists should think about screening for non-pain-related stress to facilitate treatment, prevent chronic disability, and improve quality of life.