Cocaine- and amphetamine-regulated transcript (CART) peptides are putative neurotransmitters which appear to play a role in the rewarding and reinforcing effects of both natural (food) and unnatural (psychostimulants) stimuli. There is extensive anatomical, pharmacological, and behavioral evidence supporting the importance of CART peptides in psychostimulant, namely cocaine and amphetamine, abuse. For instance, CART mRNA and peptides are found in brain regions considered important in the reward and reinforcement of psychostimulants including the ventral tegmental area and the nucleus accumbens, which are part of the mesolimbic dopamine system. Consequently, in a pharmacological sense, CART peptides have been closely linked to the actions of mesolimbic dopamine. In addition, under certain conditions, psychostimulants alter CART mRNA and peptide levels. However, the exact conditions and mechanisms are unclear and may involve CART modulation by corticosterone and/or cyclic AMP response element binding protein (CREB). Finally, behavioral studies on CART and psychostimulants suggest a modulatory role for CART in the actions of psychostimulants as central administration of CART attenuates the behavioral effects of cocaine. This review discusses the anatomical, pharmacological, and behavioral evidence implicating a role for CART peptide in the rewarding and reinforcing properties of psychostimulants.