We describe the effects of metabolic diabetic factors and sera from diabetic animals and humans on the development of early pre-implantation mouse embryos. Our studies demonstrated that 20 to 24% of control mouse blastocysts failed to develop successfully when grown for 72 h in RPMI medium supplemented with 10% fetal bovine serum. D-glucose in concentrations greater than 3 mg/ml, insulin at concentrations of 0.5 and 1.0 IU/ml, glucagon in concentrations of greater than or equal to 10 micrograms/ml, beta-hydroxybutyrate in concentrations greater than 5 mg/ml, and acetoacetate at concentrations of greater than or equal to 10 micrograms/ml were all embryotoxic, the number of underdeveloped blastocysts rising to over 50%. The combination of these factors in relatively low concentrations was highly embryotoxic, especially when accompanied by hyperglycemia. The addition, to a control medium, of serum from nondiabetic rats (in concentrations of 20%) or of nondiabetic human serum (in concentrations of 50%) did not significantly change the rate of blastocystic development. Serum from streptozotocin-diabetic rats, in the same concentrations, increased the number of undeveloped embryos to 53%. With human diabetic sera the highest embryotoxic effect was found in type I diabetes with and without ketoacidosis. In type II diabetes, embryotoxic effects, although lower, were observed among all types studied [untreated, treated with insulin or with DAONIL (Hoechst, Germany)]. A high correlation was found between the number of undeveloped embryos and the blood concentrations of metabolic diabetic factors: glucose (in type I diabetes), beta-hydroxybutyrate (in type II diabetes untreated or treated with Daonil), acetoacetate (in insulin-treated type II diabetes), and HbA1c (in both insulin-treated and in Daonil-treated type II diabetes). The possible role of diabetic metabolic factors in causing increased risk of spontaneous abortions and infertility among diabetic women is discussed.