Recent discoveries of the participation of metabolic enzymes (or homologs) and metabolic cofactors in transcriptional regulation raise the exciting possibility of a direct link between cellular metabolism and regulated gene expression. These findings also pose intriguing mechanistic questions. For instance, are the enzymatic activities of the metabolic enzymes important for transcriptional regulation? Are the homologs of those metabolic enzymes in fact enzymes? If so what are the exact roles of the enzymatic activities in transcriptional regulation? Finally, what is the role of the metabolic cofactors in gene transcription? In this article, we focus on the recent advances in deciphering the roles and mechanisms of action of metabolic cofactors and enzymes in regulated transcription.