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A comprehensive multidisciplinary review of the most relevant molecular, genetic, and behavioral approaches used to investigate the neurobiological basis of drug addiction. The authors explore the latest findings on opioid, psychostimulant, cannabinoid, alcohol, and nicotine addiction, provide fresh insights into the genetic basis of drug addiction and the new therapeutic perspectives these have opened. They describe the technology available to generate conditional knockout mice and show how these mice can reveal the molecular basis of opioid, psychostimulant, and cannabinoid addiction. They also review the different behavioral models available to evaluate the rewarding effects of drugs and analyze the genes involved in alcohol dependence.