Neuropeptides such as neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) have been implicated not only in acute regulation of stress/anxiety-related behaviors, but adaptations and changes in these neuropeptide systems may also participate in the regulation of behavior and endocrine responses during chronic stress. NPY is an endogenous anxiolytic neuropeptide, while CRH has anxiogenic properties upon central administration. Changes in these neuropeptide systems may contribute to disease states and give us indications for putative treatment targets for stress/anxiety disorders as well as alcohol/drug dependence. In this review, we briefly present these two systems and review their involvement in mediating the responses to acute and chronic stressors, as well as their possible roles in the development and progression of stress/anxiety disorders. We suggest that neuropeptides may be attractive in treatment development for stress/anxiety disorders, as well as for alcohol/drug dependence, based on their specificity and activity following exposure to external challenges, i.e. stressors, and their differential adaptations during transition from an acute to a chronic stress exposure state.