The use of substances for psychoactive effects dates to antiquity with evidence in archaeological finds of alcohol-related intoxication and possibly ritualistic use of Nymphaea caerulea in ancient Egypt and alcohol abuse in classic Greek and Roman culture. The neurobehavioral characterization of addiction encompasses a broad spectrum of features. In line with a neurobiological model of addiction, altered neurochemistry remains at the core of the acute and chronic addictive process that is so disruptive to individuals, their families, and the public. This underscores the importance of describing the addiction process through careful in-vivo neurochemical investigation, and it is fortunate that there exist today powerful imaging tools to enhance understanding of human addiction. Drugs of abuse that include methamphetamine, opioids, nicotine, methylenedioxymethamphetamine (MDMA), cannabinoids, and alcohol are discussed. Gender differences in response to acute and long-term exposure may be subserved by neurochemical differences as well.