Opiates are powerful analgesics commonly used clinically to relieve pain. However, their repeated administration can lead to the development of drug dependence. During this transition from casual use to abuse, individuals initially respond to opioids as positively rewarding. Tolerance and then physical dependence develop over time, with withdrawal symptoms seen upon drug cessation. Drug craving, induced either by conditioned cues, stressors, or administration of the drug itself, often lead to compulsive drug-seeking behavior, which, in turn, may lead to drug taking and relapse. Three major animal models have been widely used to investigate the behavioral properties and neurobiological mechanisms of drug addiction, i.e., self-administration (SA), conditioned place preference (CPP), and intracranial self-stimulation (ICSS). Generally, operant SA procedures are used to model reward (reinforcement) and relapse (reinstatement) (see Note 1 ). CPP is a relatively simple Pavlovian reinforcement procedure that can be used to evaluate the effects of environmental cues on both the positive rewarding and negative or aversive reinforcing properties of opiates (see Chapter 18 ). Finally, ICSS is commonly used to map specific brain reward systems or circuits and their potential modification during the stages of drug dependence. The particular research question, of course, determines the choice of the methodology employed.