Despite the fact that fetal drug exposure is common, the disposition of drugs in the fetus is poorly understood. This study aimed to investigate fetal placental and non-placental disposition of rosiglitazone in the pregnant ewe. Steady state was reached after day 5 of fetal infusion, and were ~1.8 fold higher than maternal concentrations (P < 0.001). The AUC for fetal rosiglitazone concentration throughout the infusion was inversely correlated with placental and fetal weight. Metabolic activity of the fetal liver microsomes were ~25 fold lower than maternal microsomes (P < 0.001). The findings suggest that trans-placental transfer is the major route through which rosiglitazone is cleared from the fetal compartment, while non-placental hepatic elimination makes only a minor contribution. This supports a limited capacity of the fetus for eliminating this class of drugs, and highlights the potential for drug toxicity when administering pharmacotherapy to the mother/fetus in human pregnancy.