The transcription factor CtBP associates with transcriptional repressors for the regulation of genes involved in development, cell cycle regulation, and transformation. Zhang et al. show that the corepressor activity of CtBP can be regulated by the redox state of the cell. Mammalian CtBP is regulated by physiological concentrations of nuclear nicotinamide adenine dinucleotides (NADs). When the nuclear concentration of free NAD and NADH increases, CtBP increases its affinity for viral and cellular repressors and represses transcription. This regulatory mechanism suggests how protein interactions might respond to metabolic balances for the regulation of transcription.