Motivational mechanisms that underlie escalation of drug seeking and relapse are complex, and vary both between individuals, and, over time, within an individual. We have reviewed recent additions to a growing number of stress-related neuropeptide modulators that, based on preclinical studies, have been suggested to contribute to drug seeking and taking. These findings hold the promise of expanding therapeutic options in addictive disorders, but the promise comes with considerable challenges. The multiple systems involved, their interactions, and the multiple levels at which they can influence behavior should serve as a warning against overly simplistic predictions of therapeutic potential. Personalized medicine approaches that take in account genetic variation in genes encoding elements of these systems, and ways in which environmental exposures (including drug exposure) influence them will likely become critical determinants of efficacy. Basic science will be vital to determine the relative impact of genetics, environment, and drug use history to the function of each system. Once such data emerge, they will hopefully help guide clinical development.
