Cell-cycle analysis of nuclei obtained from the circulating erythroblasts (gestational day (GD) 11-16), livers (GD 14-19), and whole embryos (GD 10-13) or remaining (extrahepatic) tissues (GD 14-16) of rat embryos/fetuses revealed age- and tissue-dependent variations in the relative percentages of cells in the G0/G1, S, and G2/M phases of the cell cycle. To determine how these developmental and organ-specific cell-cycle variations affect toxic response, we sampled GD 11-13 embryos 6 hr after maternal administration of a teratogenic dose of 5-fluorouracil (5-FU), a thymidylate synthetase inhibitor that induces S-phase accumulation. The results indicate that, on a relative basis, the amount of induced S-phase accumulation in erythroblasts and whole embryos 6 hr postdosing increased with development. In contrast, a time course of hepatic cell-cycle distributions from GD 14 embryos after maternal dosing revealed that S-phase accumulations occurred at an earlier time, possibly as a consequence of a higher proliferative rate. These findings suggest that the extent of observed toxicant-induced cell-cycle perturbations depends on gestational age, tissue type, and the time of sampling.