From the perspective of psychobiological stress research we present a brief overview of findings documenting a significant impact of genetic factors on the activity of the hypothalamus-pituitary-adrenal (HPA) axis. Quantitative genetic studies in twins as well as association studies, primarily on polymorphisms in the glucocorticoid receptor gene, are depicted. Recent findings suggest that the collaboration of psychobiology and molecular genetics is a promising interdisciplinary approach that will significantly contribute to the understanding of the mechanisms underlying the link between stress, the HPA axis, and HPA-related clinical states.