Cytochrome P450 (CYP) is a complex gene superfamily of proteins that metabolizes a myriad of endogenous and exogenous substrates. Liver-enriched transcription factors (LETF) play a role in the constitutive and tissue-specific expression of hepatic genes. In this review, six families of LETF that play a role in the tissue-specific, developmental, sexual and temporal regulation of CYP are discussed.