One strategy in the search for a pharmacotherapy for cocaine abuse and dependence has been to use drugs with a similar mechanism of action as cocaine, or agonist substitution therapy. Research has indicated that cocaines behavioral effects are primarily a result of its blockade of the dopamine (DA), serotonin (5-HT) and norepinephrine (NE) transporters. Therefore, drugs that act either directly or indirectly at these monoamine systems have been investigated for their potential as replacement medications for cocaine addiction. The intent of this review was to present data from animal models that assessed the reinforcing effects of these monoamine agonists using drug self-administration, and the rewarding effects, using the conditioned place preference paradigm. Those data were then compared to the abuse liability of the selected drugs in humans and to their efficacy as therapeutics for treating cocaine addiction to determine if animal models of reinforcing and rewarding effects were predictive of these drugs effects in humans. Fourteen drugs with a primary mechanism of action at either the DA, 5-HT or NE systems were identified that had been tested as potential treatments for cocaine addiction and had also been evaluated in either the self-administration or conditioned place preference paradigms in animals. From these comparisons, it was concluded that the animal models were, in general, predictive of the abuse liability of these monoamine agonists in humans. However, monoamine agonists with reinforcing or rewarding effects did not affect the desired treatment outcomes for cocaine addiction.