There has been an emphasis in the literature on the constructs of positive and negative reinforcement. This paper addresses both of these constructs and the neurochemical substrates for positive and negative reinforcement associated with drug addiction; it then introduces another chemical that may contribute to what is happening in addiction. For opiate drugs and alcohol, multiple neurotransmitter systems and neurotransmitters have been implicated in their reinforcing effects. Many specific systems in the brain mediate these drug actions. First is the mesolimbic dopamine system, which projects from the VTA to the NAc and amygdala. There are also opiate peptide systems, which are natural substances in the brain. The acute reinforcing actions of drugs, however, are only part of the motivation for drug taking. In addition to changes in the neurochemical systems associated with acute drug reinforcement, other neurochemical components may contribute to a negative effect, which motivates drug taking to mitigate the negative effects. Another neurotransmitter that has been implicated in the affective responses associated with chronic drug use is called corticotropin-releasing factors (CRF). CRF has been characterized in the pituitary and the hypothalamus, where it controls the pituitary adrenal response to stressors. CRF is also localized outside the pituitary in the limbic system, where it is apparently involved in behavioral responses to stressors. There is growing evidence that brain CRF is activated in response to long-term drug treatment. Finally, other neurotransmitters besides dopamine and CRF in the NAc-amygdala continuum respond to chronic drug treatment. They include opioid peptides, serotonin, and perhaps even GABA. 4 tables