Lipophilic endocrine signals in metazoans, including the steroid, thyroid, and retinoid hormones, alter gene expression in target cells by binding to and modulating the activity of nuclear receptor (NR) transcription factors . In vertebrates, xenobiotic and pharmacologic compounds can regulate the expression of protective metabolic enzymes via specific "xenobiotic sensing" NRs [2-4]. Here, we report evidence suggesting that this activity is an ancient conserved function for the NR class containing these receptors. Specifically, we show that a Caenorhabditis elegans member of this NR class, nhr-8, is required for wild-type levels of resistance to the toxins colchicine and chloroquine. The nhr-8 promoter is active in the nematode gut, a tissue that also expresses the ABC transporter, PGP-3, which contributes to defense against these toxins . In contrast to pgp-3 mutants, nhr-8 mutants are not more sensitive than wild-type to pyocyanin-dependent killing by the pathogenic bacterium Pseudomonas aeruginosa. We conclude that NHR-8 functions in the nematode xenobiotic defense system and that NHR-8 and PGP-3 have overlapping, but distinct, spectra of toxin specificity.