Transcription factors are key mediators of the genetic programs that underlie human development and physiology. Mutations in genes that encode transcription factors or in DNA sequences to which these factors bind may adversely affect gene expression and result in disease. Mutations in genes encoding transcription factors often have pleiotropic effects because each transcription factor is involved in the regulation of multiple genes. For several transcription factors, germline mutations have been shown to result in malformation syndromes whereas somatic mutations in the same genes contribute to the multistep process of tumorigenesis. The study of transcription factors and their involvement in human disease thus provides insight into the molecular mechanisms underlying human development, physiology, dysmorphology, and oncology.