There are currently effective, U.S. Food and Drug Administration (FDA)-approved therapies for alcohol, nicotine, and opioid addiction. In some cases these therapeutics were rationally designed and tested using a combination of various animal models of addiction. In many cases, however, effective drug therapies for addiction were derived from the testing of compounds developed for other CNS disorders (e.g., analgesics and antidepressants), which were tested clinically in the absence of prior animal research using addiction models. This article will review the development of eight compounds that are currently most effective in the treatment of alcohol, opioid, and nicotine addiction with an emphasis on pharmacological mechanisms as well as the utility of animal models of addiction in the development of these therapeutics. In contrast to these successes, animal research has identified a number of promising medications for the treatment of psychostimulant addiction, none of which have proven to be effective clinically. This raises questions about the validity of current animal models of psychostimulant addiction. A specific example of an apparently promising pharmacotherapeutic for cocaine addiction (the D1 dopamine receptor antagonist ecopipam) that failed clinically will be examined to determine if this truly represents a challenge to the predictive validity of current models of cocaine addiction. In addition, the development of promising cocaine addiction therapeutics derived from animal research will be reviewed.