Among the human liver cytochrome P450s (P450s), a family of microsomal hemoproteins responsible for catalyzing the oxidative metabolism of clinically used drugs and environmental chemicals, attention has been focused on CYP3A, a form that is the most abundant and is inducible by many of its substrates. From early pharmacological studies that demonstrated induction of CYP3A by glucocorticoids and, paradoxically, by antiglucocorticoids, the existence of a nonclassical glucocorticoid receptor mechanism was inferred and prompted research that culminated in the identification of a unique member of the nuclear receptor family, the pregnane X receptor (PXR; NR1I2). It has become increasingly evident that PXR as well as other nuclear receptors mediate CYP3A induction in a unique and complex manner including inducibility by structurally diverse compounds and striking interspecies differences in induction profiles. Future understanding of the role of nuclear receptors in regulating expression of CYP3A and other genes of the P450 family offers an exciting promise of further defining the physiologic function and interindividual differences of CYP3A in health and disease.