The fundamental role of transcription and the recognition of transcription factors and co-activators as important control elements of cell growth, differentiation, and apoptosis created an ever-increasing interest for these proteins as potential pharmaceutical targets for therapeutic intervention in cancer. The vast array of information available for their molecular structure and mode of action in various biological contexts, combined with the new opportunities offered by the technologies of structure-based drug design, computer-aided modeling, and functional genomics/proteomics are creating an exciting opportunity for the development of a novel generation of highly selective therapeutics. This lecture will cover several fundamental aspects of transcription factor-based gene regulation and provide an example of targeting transcription factor-coactivator interactions by exploiting the tissue-specific and gene-specific differences in transcriptional machinery composition.