Cumulative acute psychosocial stress is thought to promote the development of a range of disorders which suggests that biomarkers for the physiological response may become valuable tools for biomedical research and development. The search for these biomarkers has been aided by the development of a standardised protocol for inducing psychosocial stress that combines social-evaluative threat and uncontrollability, i.e., the Trier Social Stress Test (TSST). Among other biological markers of acute stress, this test induces significant changes of the hypothalamus-pituitary-adrenal axis (HPAA), which is thought to play a pivotal role in the generation of stress-associated pathologies. The HPAA responses show differences between patients and healthy subjects as well as between pathologies. Moreover, gender, age, personality traits, social environment, and genotype can also shape the individual's acute stress response triggered by the TSST. Characterization of the roles and interactions of these factors in generating a dysregulation of the neuroendocrine responses to acute psychosocial stress await longitudinal studies.