Transcription factors act to regulate gene expression. Many transcription factor families have been discovered based on their roles in cell cycle events involved in development and oncogenesis. In post-mitotic neuronal cells, however, many transcription factor genes are "trans-synaptically" regulated: their patterns of expression can be dramatically altered by extracellular stimuli. Transcription factor proteins can then potently influence expression of other genes, whose products can directly alter neuronal function. The central nervous system (CNS) displays varying degrees of neuroplasticity in adult life. Flexible neurochemical pathways that link extracellular stimuli to long-term modifications in neuronal functions are likely to contribute substantially to this neuroplasticity. This review summarizes evidence supporting central roles for transcription factors in such neurochemical cascades. It furthermore illustrates how drugs of abuse can trigger and modulate neuroadaptive processes that could conceivably contribute to clinically relevant addiction phenomena such as craving, tolerance, sensitization, and withdrawal.