Precise timing of the teratogenic period in diabetic pregnancy is of clinical importance since correction of the glucose intolerance during this period may protect the offspring from malformations. An experimental approach to elucidate this problem with regard to skeletal development was made in groups of pregnant streptozotocin-diabetic rats (MDI), which were treated with daily insulin injections except for a 2-day period in the first half of pregnancy. The degree of metabolic derangement was estimated by measurements of serum glucose concentrations. During the insulin-free period, the rats showed severe hyperglycemie (>20 mM) while during ongoing insulin treatment, only brief periods of hyper- or hypoglycemia were observed. Insulin treatment was withdrawn successively between gestational days 3 and 12. Control groups consisted of normal pregnant rats (N) or pregnant rats with manifest diabetes (MD) without insulin treatment. The serum glucose levels of the N animals were below 6 mM while those of the MD animals were above 25 mM throughout pregnancy. Skeletal malformations in the viable offspring were recorded on gestational day 20 after Alizarin staining of calcified ossification centers, which also allowed an estimate of skeletal development as a whole. Untreated diabetes in the MD rats induced a high rate of fetal resorptions, a decrease in fetal weight and viability, as well as retardation of skeletal development. Intermittent insulin treatment in the MDI rats ameliorated, but did not abolish, these changes. In the MD group 9 of 48 viable fetuses showed severe malformations of either the lower jaw (micrognathia) or of the lumbosacral region (caudal dysgenesis). No skeletal malformations were observed in 151 offspring of the N group. Among the MDI animals, skeletal malformations occurred in 2 of 52 viable fetuses with interruption of maternal insulin treatment on gestational days 2–3, in 7 of 118 fetuses with interruption of insulin on days 4–5, and in 4 of 77 fetuses with interruption on days 6–7. No skeletal malformations were seen in a total of 75 MDI fetuses after interruption of insulin treatment on either days 8–9 or 10–11. However, a high rate of resorptions was also seen in these two groups. These observations strongly suggest that in rats, the teratogenic impact of maternal diabetes on embryonic skeletal development manifests itself at an unexpectedly early embryonic age and that correction of metabolism with insulin during this critical period may protect the offspring from malformations.