A prominent feature of drug addiction is that drug-associated cues can elicit drug-seeking behaviors and contribute significantly to the high propensity to relapse. We have been investigating the notion that the dopamine D1 receptor and the immediate early gene product c-Fos expressed in D1 receptor-bearing neurons mediate the development of persistent neuroadaptation in the brain dopamine system by regulating cell signaling and gene expression. We generated and analyzed genetically engineered mouse models and found that the D1 receptor and c-Fos expressed in D1 receptor-bearing neurons mediate the locomotor sensitization and reinforcing effects of cocaine. Moreover, these molecules regulate cocaine-induced dendritic remodeling, electrophysiological responses, and changes in cell signaling and gene expression in the brain. Notably, a lack of Fos expression in D1 receptor-bearing neurons in mice results in no change in the induction but a significantly delayed extinction of cocaine-induced conditioned place preference. These findings suggest that D1 receptor-mediated and c-Fos-regulated changes in cell signaling and gene expression may play key roles in the extinction process, and they provide a foundation for further exploring mechanisms underlying extinction of cue-elicited cocaine seeking.