Diabetic embryopathy reflects a scientific enigma--how does a seemingly rich intrauterine environment manage to disturb the development of the embryo? Which compounds in that environment may be teratogenic--and how shall we find them? How can we investigate a putative dose-response nature of the teratogen, i.e., how can we monitor the effects of varied severity of the diabetic state (which can be varied in a number of metabolic ways) on the embryonic development? Here, the whole embryo culture (WEC) technique provides an excellent tool for such studies. WEC is thus currently used to investigate the effect of graded levels of diabetes (e.g., hyperglycemia, hyperketonemia, increased branched chain amino acid (BCAA) levels), and putative antiteratogenic agents (antioxidants, folic acid, arachidonic acid, inositol), as well as the effect of different embryonic genotypes on diabetes-induced (mal)development. WEC is the only method, which is able to couple specific embryonic maldevelopment to precise changes in substrate levels or the (epi)genotype of the embryo. Using this method, we have been able to demonstrate that a diabetic environment--culture of embryos in serum from diabetic animals or in serum with increased levels of glucose, β-hydroxybutyrate or α-ketoisocaproic acid (KIC)--causes increased embryonic maldevelopment, and that this dysmorphogenesis is blocked by the addition of ROS scavenging agents to the culture medium. Genetically, others and we have demonstrated that Pax-3 downregulation predisposes for diabetes-induced dysmorphogenesis.