Longitudinal study of 2 cohorts of children selected in the second or third year of life to be extremely cautious and shy (inhibited) or fearless and outgoing (uninhibited) to unfamiliar events revealed preservation of these 2 behavioral qualities through the sixth year of life. Additionally, more of the inhibited children showed signs of activation in 1 or more of the physiological circuits that usually respond to novelty and challenge, namely, the hypothalamic-pituitary-adrenal axis, the reticular activating system, and the sympathetic arm of the autonomic nervous system. It is suggested that the threshold of responsivity in limbic and hypothalamic structures to unfamiliarity and challenge is tonically lower for inhibited than for uninhibited children.