In this chapter, we discussed the critical role of gene expression regulation in cellular homeostasis. We focused on the transcriptional control of gene expression, which is the primary regulatory step. Eukaryotic polymerase RNA II requires the collaboration of transcription factors, which can be classified into basal transcription factors and gene-specific transcription factors. Basal transcription factors recruit the RNA polymerase II complex to the minimal promoter, while gene-specific transcription factors activate or repress basal transcription. These transcription factors bind to regulatory sequences organized in regulatory modules along the DNA. Mutations in transcription factors have been linked to a growing list of human diseases, often resulting in pleiotropic effects. These transacting factors control the expression of multiple genes, often in conjunction with activators. Overexpression or mutations of transcription factors are also implicated in tumorigenesis. This chapter provides an overview of human diseases associated with mutations in transcription factor genes or their cognate binding sites.