Cells respond to external signals by either activating or inhibiting key regulatory proteins of gene expression called transcription factors (TFs). Abnormal expression of these factors play a critical role in many human cancers. Recently, many TFs have been identified and their structure-function relationship has been characterized. Such new information has been useful in designing new chemotherapeutic drugs targeting these regulatory proteins. This review discusses the use of dominant-negative (DN) mutants of TFs as inhibitors of cell growth, as well as possible strategies for screening potential inhibitors of TF activity.