This paper outlines a strategy and process for proactive nonclinical assessment of drug abuse and dependence liability of new compounds intended for clinical use. Documentation of the potential for causing abuse and dependence liability is required for registration of a new drug; hence, proactive timing and planning of these studies allows for appropriate documentation of nonclinical as well as clinical data in time for registration. In cases for which an abuse and dependence liability label may not be acceptable, a proactive approach to abuse and dependence liability assessment allows for replacement of selected compounds at an early stage of development, thereby saving time and resources and avoiding late attrition.