The ability to alter gene expression with synthetic ligands is a complex but important problem in the post-genomic era, as it creates a foundation for rational development of new therapies. Because regulation of gene expression is critical for cellular existence, with aberrant genes often regarded as a cause in development of diseases, one of the primary goals in the biomedical fields has been to discover methods of altering gene expression in malignant cells while leaving normal cells unaffected. To address this goal, we seek to uncover highly specific small molecule-based transcriptional regulators which to date come primarily from nature and exist only for a limited set of transcription factors. Our rational design strategy explores unique transcription factor-coactivator interactions by exploiting the tissue-specific and gene-specific differences in the transcriptional machinery composition. Using small molecules as tools, we aim to answer fundamental questions surrounding gene and cell cycle regulation at the molecular level.