Drug and alcohol abuse represents a major public health burden in the United States and is responsible for a significant loss of productivity among U.S. citizens. As such, effective strategies will need to be developed that address the social and biomedical consequences of drug abuse in the United States, including the discovery of pharmacotherapies and cognitive behavioral interventions that decrease drug or alcohol intake, help maintain sobriety, and prevent or address the neurobiological sequelae associated with repeated drug exposure. These pre-clinical studies employed the curve-shift method of intracranial self-stimulation in mice to probe the behavioral effects of rewarding substances on mesocorticolimbic circuitry involved in positive reinforcement in order to 1) describe the reward-potentiating effects of previously uncharacterized drugs of abuse (e.g. the synthetic stimulant mephedrone); 2) test the utility of candidate pharmacotherapies (e.g. neurokinin-1 receptor antagonists or the atypical antiepileptic levetiracetam) to blunt the positive subjective effects of drugs or alcohol; or 3) determine pharmacogenetic differences in acute drug responses using humanized mice modeling known genetic variants associated with substance abuse or treatment efficacy (e.g. the mu opioid receptor gene (OPRM1) A118G polymorphism). Taken together, these investigations reflect the neuropharmacological utility of ICSS as a translational tool to help address unmet needs in the treatment of substance use disorders.