Exposure to an uncontrollable stressor elicits a constellation of physiological and behavioral sequel in laboratory rats that often reflect aspects of anxiety and other emotional disruptions. We review evidence suggesting that plasticity within the serotonergic dorsal raphe nucleus (DRN) is critical to the expression of uncontrollable stressor-induced anxiety. Specifically, after uncontrollable stressor exposure subsequent anxiogenic stimuli evoke greater 5-HT release in DRN terminal regions including the amygdala and striatum; and pharmacological blockade of postsynaptic 5-HT(2C) receptors in these regions prevents expression of stressor-induced anxiety. Importantly, the controllability of stress, the presence of safety signals, and a history of exercise mitigate the expression of stressor-induced anxiety. These stress-protective factors appear to involve distinct neural substrates; with stressor controllability requiring the medial prefrontal cortex, safety signals the insular cortex and exercise affecting the 5-HT system directly. Knowledge of the distinct yet converging mechanisms underlying these stress-protective factors could provide insight into novel strategies for the treatment and prevention of stress-related psychiatric disorders.