Context: Pollutants and toxicants passing from the mother to the fetus may damage developing organ systems. The human fetal liver is both a potential target organ and a critical defense against exposure to such xenochemicals. Objective: The aim of the study was to determine the effects of human fetal toxicant exposure, via maternal smoking, on metabolic enzyme transcripts in the fetal liver. Design and Setting: We conducted an observational study of mRNA transcripts and proteins in livers from second trimester fetuses at the Universities of Aberdeen and Glasgow. Patients/Participants: Liver samples were taken from 55 normal fetuses from women undergoing second trimester elective termination. Main Outcome Measures: Housekeeping genes for normalization were identified by GeNorm and NormFinder. Levels of mRNA transcripts encoding 15 metabolic enzymes and three xenobiotic receptors were measured. Expression of representative proteins was shown by Western blotting. Results: Eighty-nine percent of measured transcripts were detectable in the human fetal liver. Eight transcripts showed significant sex-specific differences in expression levels (EPHX1, GSTA1, GSTT1, AHR, AS3MT, GLRX2, GGT1, CAR). In male fetuses, maternal smoking was associated with a decrease in expression of three transcripts (GGT1, CYP2R1, CAR) and an increase in eight transcripts (CYP1A1, EPHX1, NQO1, GSTP1, GSTT1, AHR, AS3MT, GLRX2). In the female, CYP3A7 and EPHX1 were increased in smoke-exposed fetuses. Conclusions: The human fetal liver expresses a wide array of metabolic enzymes, with sex differences apparent in 44% of the transcripts measured. Exposure of the fetus to pollutants/toxicants is associated with significantly altered transcript expression, with the more marked response in the male potentially affecting levels of endogenous factors involved in fetal growth.