Chronic administration of opiates or cocaine has been shown to alter the activity or expression of diverse types of cellular proteins in specific target neurons within the central nervous system. Prominent examples include signaling proteins, such as receptors, G proteins, second-messenger synthetic enzymes, and protein kinases. It is now increasingly possible to relate particular molecular adaptations to specific behavioral actions of drugs of abuse in animal models of addiction. In addition, recent work has focused on a role for transcription factors, and the associated alterations in gene expression, in mediating part of this long-lasting, drug-induced molecular and behavioral plasticity.