In mammalian cells, protein de novo synthesis is mainly regulated at the stage of gene transcription by RNA polymerase II in the nucleus. Transcription factors are proteins that bind to the specific nucleotide sequences at promoter or enhancer regions on target genes to control the transcription of mRNA from genomic DNA. In this article, we have outlined the signal responsiveness of different transcription factors to particular drugs in the brain. Nuclear transcription factors rapidly respond to a variety of extracellular signals carried by neurotransmitters, hormones and autacoids as a third messenger in frequent situations. Translated proteins are responsible for a number of physiological and pathological events for a long period in the brain. We have also discussed possible involvement of transcription factors in molecular mechanisms underlying development of tolerance and dependence to drugs following acute and chronic administration.