This review presents new aspects to understanding the neuroendocrine regulation of equine stress responses, and their influences on the physiological, pathophysiological, and behavioral processes. Horse management, in essence, is more frequently confirmed by external and internal stress factors, than in other domestic animals. Regardless of the nature of the stimulus, the equine stress response is an effective and highly conservative set of interconnected relationships designed to maintain physiological integrity even in the most challenging circumstances (e.g., orthopedic injuries, abdominal pain, transport, competitions, weaning, surgery, and inflammation). The equine stress response is commonly a complementary homeostatic mechanism that provides protection (not an adaptation) when the body is disturbed or threatened. It activates numerous neural and hormonal networks to optimize metabolic, cardiovascular, musculoskeletal, and immunological functions. This review looks into the various mechanisms involved in stress responses, stress-related diseases, and assessment, prevention or control, and management of these diseases and stress. Stress-related diseases can not only be identified and assessed better, given the latest research and techniques but also prevented or controlled.