We hypothesized that bone evolved, in part, to enable bony vertebrates to escape danger in the wild. In support of this notion we show here that a bone-derived signal is necessary to develop an acute stress response (ASR). Indeed, exposure to various types of stressors in mice, rats (rodents) and humans leads to a rapid and selective surge of circulating bioactive osteocalcin because stressors favor the uptake by osteoblasts of glutamate, which prevents inactivation of osteocalcin prior to its secretion. Osteocalcin permits manifestations of the ASR to unfold by signaling in post-synaptic parasympathetic neurons to inhibit their activity, thereby leaving the sympathetic tone unopposed. Osteocalcin is also engaged in a complex cross talk with the other principal endocrine regulator of the ASR, the hypothalamic-pituitary-adrenal axis. Exogenous osteocalcin stimulates an increase in circulating adrenal steroids and Ocn-/- mice born of Ocn-/- mothers exhibit a severe developmental defect in adrenal steroidogenesis of corticosterone and aldosterone. Like wild-type animals, adrenalectomized rodents and adrenal-insufficient patients can develop an ASR, and genetic studies suggest that this is due to their high circulating osteocalcin levels. We propose that osteocalcin defines a bony vertebrate specific endocrine mediation of the ASR. Together these results demonstrate a role for bone in the physiology of danger.