Abstract: Purinergic signaling is involved in multiple physiological and pathological processes. Psychological stress, as an inharmonious state in response to stressors, is closely related to the function or dysfunction of purinergic signaling. Abnormal expression of ATP interceptors caused by stress leads to psychological stress-related diseases, such as anxiety, depression, post-traumatic stress disorder and schizophrenia. Recent studies demonstrate that a complex network of purinergic signaling (such as ATP, adenosine and P2X2R, P2X3R, P2X4R, P2X7R, A1R, A2AR) plays a key role in psychological stress, but the specific mechanism remains to be further studied. And few studies focus on the application of ATP real-time detecting to psychological stress animal models, so the specific biological role of ATP in the process of stress is still unknown. This review will summarize the relationship between purinergic signaling and psychological stress and propose to apply the duplicate ATP real-time detection technology and purinergic compounds on psychological stress research in order to provide novel potential targets for the treatment of stress-related diseases.