Animals models have begun to provide insights into the neurobiological basis of reinforcement in drug addiction. The reinforcing effects of indirect sympathomimetics such as cocaine and amphetamine appear to depend on release of dopamine in the terminal fields of the mesocorticolimbic dopamine system. The acute reinforcing effects of opiates involve not only an activation of dopamine, but also dopamine-independent elements in the terminal regions of the mesocorticolimbic dopamine system. Nicotine's reinforcing effects may involve both dopaminergic and opioid peptidergic systems. Ethanol's reinforcing effects may result from multiple neurotransmitter interactions including gamma-aminobutyric acid, glutamate, dopamine, opioid peptides, and serotonin. Subtle changes in neurochemical function and signal transduction and transcription mechanisms in sensitive neuronal elements in the extended amygdala may be mediators of chronic drug action that lead to vulnerability to relapse and may provide exciting insight into the neuroadaptations associated with drug addiction.