This review primarily focuses on our recent findings in bidirectional translational research on opiate and cocaine addictions. First, we present neurobiological and molecular studies on endogenous opioid systems (e.g. proopiomelanocortin, mu opioid receptor, dynorphin, and kappa opioid receptor), brain stress-responsive systems (e.g. orexin, arginine vasopressin, V1b receptor, and corticotropin-releasing factor), hypothalamic-pituitary-adrenal axis, and neurotransmitters (especially dopamine), in response to both chronic cocaine or opiate exposure and to drug withdrawal, using several newly developed animal models and molecular approaches. The second aspect is human molecular genetic association investigations including hypothesis-driven studies and genome-wide array studies, to define particular systems involved in vulnerability to develop specific addictions, and response to pharmacotherapy.