Detecting and quantifying pain in infants and young children is a complex task because young children cannot communicate this subjective phenomenon. In the 1950s, it was postulated that there might be "wound hormones" produced in injured tissues that activated the pituitary-adrenal axis. Research in adults demonstrated that plasma levels of different hormones, including corticosteroids, cathecholamines, growth hormone, and insulin, changed in response to emotionally and physically stressful stimuli. Stress response is the term given to those hormonal and metabolic changes that follow injury or trauma, but the debate as to whether increased stress response is a sign of pain or whether decreased stress response is a sign of diminished pain has not been resolved yet. Following the study of systemic response to surgery, the ability of anesthetic agents to substantially attenuate intraoperative and postoperative stress response has been reported. In newborns, a strong correlation between preoperative stress and postoperative complication rate was found. The full extent of the vulnerable infant's pain is still poorly understood, but further research of known biologic markers and newly discovered ones could promote our understanding of the pain response and increase our ability to prevent undesirable outcome.