The pregnane X-receptor (PXR) and the constitutive androstane receptor (CAR) are orphan nuclear receptors activated by a variety of ligands. Currently it remains uncertain whether these receptors have a high-affinity ligand or instead function as more generalized steroid/xenobiotic sensors. Both receptors are important regulators of several steroid and xenobiotic detoxification enzymes and transporters (phases I-III) in the liver and intestine and thus are important regulators of adaptation to chemical stress. The detoxification proteins induced are responsible for the metabolism, deactivation and transport of bile acids, thyroid and steroid hormones, numerous environmental chemicals, and several drugs. PXR and CAR received their names because of steroid ligands that activate and inhibit their transcriptional activity, respectively. Interestingly, some steroids and steroid mimics activate one or both receptors, including several endocrine disrupting chemicals. Environmental estrogens, such as the pesticides methoxychlor, endosulfan, dieldrin, DDT, and the plasticizer nonylphenol activate either PXR or both PXR and CAR. Because PXR and CAR are activated by numerous steroids and endocrine disrupters, it appears that these receptors protect the integrity of the endocrine system. They recognize an increase in steroid-like chemicals and, in turn, induce detoxification. Furthermore, PXR and CAR induce enzymes, such as the CYP2B and CYP3A family members, responsible for the metabolism of steroid and thyroid hormones and this may alter their normal physiological function. This review summarizes the available data on the activity of endocrine disrupters and endocrine active chemicals on PXR and CAR, examines the role of PXR and CAR in protection from these chemicals, and evaluates potential adverse physiological consequences of PXR and CAR activation.