Physiological hyperarousal and hyperresponsivity, in terms of hypothalamic-pituitary-adrenal axis (hpa-axis) and autonomic (especially parasympathetic) function, are associated with symptoms of depression. Although it has often been suggested, it remains unknown whether differences in physiological stress reactivity reflect the level of an individual's vulnerability to psychopathology, and constitute a causal factor in its development. The main problem is that associations between the functioning of stress-axes and psychopathology have typically been found in cross-sectional studies. The purpose of this symposium is to characterize the chain of events that connect stress, stress reactivity and psychopathology. We have therefore invited speakers who are well-informed about the gene-environment correlations and interactions that determine stress-reactivity, and about the consequences of alterations in stress-reactivity on internalizing disorders. Special emphasis will be on interdisciplinary research, connecting data from genetic epidemiology and social psychology to biomedicine. Recent advances in the study of molecular genetics, gene-environment interplay, and stress-reactivity based endophenotypes offer the opportunity to make a forward leap in understanding through which mechanisms depression develops.