Loneliness becomes more prevalent as youth transition from childhood into adolescence. A key underlying process may be the puberty-related increase in biological stress reactivity, which can alter social behavior and elicit conflict or social withdrawal (fight-or-flight behaviors) in some youth, but increase prosocial (tend-and-befriend) responses in others. In this article, we propose an integrative theoretical model that identifies the social, personality, and biological characteristics underlying individual differences in social--behavioral responses to stress. This model posits a vicious cycle whereby youth who respond to stress with fight-or-flight tendencies develop increasing and chronic levels of loneliness across adolescence, whereas youth who display tend-and-befriend behaviors may be buffered from these consequences. Based on research supporting this model, we propose multiple avenues for intervention to curtail the prevalence of loneliness in adolescence by targeting key factors involved in its development: social relationships, personality, and stress-induced behavioral and biological changes.