Recent evidence enriches our understanding of the molecular sites of action of cocaine reward and locomotor stimulation. Dopamine transporter blockade by cocaine appears a sufficient explanation for cocaine-induced locomotion. Variation in DAT appears to cause differences in locomotion without drug stimulation. However, previously-held views that DAT blockade was the sole site for cocaine reward have been replaced by a richer picture of multitransporter involvement with the rewarding and aversive actions of cocaine. These new insights, derived from studies of knockout mice with simultaneous deletions and/or blockade of multiple transporters, provide a novel model for the rewarding action of this heavily-abused substance and implicate multiple monoamine systems in cocaine's hedonic activities. Cocaine is a prototypical psychomotor stimulant that increases locomotor activity and elevates mood with rewarding euphoria.1 It also produces fearful and jittery aversive effects in many who take it.2,3 Cocaine blocks monoamine uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET), and can also block ligand-and voltage-gated channels with somewhat lower potencies. 4 Understanding the relationships between cocaine's molecular actions and its psychomotor stimulant and aversive properties has remained surprisingly incomplete. This review focuses on recent advances in our understanding of the complex relationships between cocaine's molecular actions and its locomotor stimulant, rewarding and aversive properties.The 'DAT-is-it' hypothesis drove thinking about cocaine reward for at least a decade, ideas widely linked to Kuhar, Spealman and their colleagues 4-8 who gathered evidence from structure-activity relationships of transporter-blocking compounds with differential potencies at DAT, SERT and NET. They examined relationships between potencies of these compounds in tests of reward and binding affinities at each of the monoamine transporters. They each identified the best correlations for the rewarding effects of cocaine with DAT blockade. These authors also cited prior work from lesion studies 9-12 and electrical brain stimulation studies [13][14][15][16][17] This 'DAT-is-it' hypothesis was a major motivation for work that resulted in cloning DAT cDNAs, genes and gene variants in our laboratory and others. [23][24][25][26][27][28][29][30] It drove characterization and study of DAT gene variants in humans 29,31-53 and animal models. 54,55 It led to the production and characterization of DAT-over-and under-expressing and DAT-knockout mice strains. [56][57][58][59] These studies revealed an exquisite DAT-dependence of cocaine's locomotor stimulation. By contrast, they also produced surprising results that refuted the strong 'DAT-is-it' hypothesis of cocaine reward. Cocaine-induced locomotion: DAT is itDAT variation in humans and mice links robustly with variation in both baseline locomotion and/or psychostimulant-induced locomotor activities. Three strains of DAT knockout ...