The toxicity of the synthetic estrogens diethylstilbestrol (DES), and ethynylestradiol (EE), and the antiestrogen clomiphene citrate (CC) was evaluated by assessing postnatal uterine growth and development prior to the onset of puberty in the rat. Both DES and EE, administered during the neonatal period (postnatal days 1-5), initially increased uterine weight and luminal epithelium hypertrophy. However, uterine weight declined in both DES- and EE-treated animals and fell below controls beyond day 11. Luminal epithelium stimulation generally paralleled uterine weight changes. Precocious development of uterine glands occurred after estrogenization (compared to untreated controls), but subsequently gland numbers were approximately 60% of control levels. Neonatal CC exposure induced only slight uterine weight gain but caused prolonged luminal epithelium hypertrophy and inhibited uterine gland genesis. Luminal epithelium hypertrophy appears to be a useful measure of antiestrogen activity. These data demonstrate the toxicity of DES and EE as assessed by altered prepubertal uterine gland development. Additionally, the inhibition of uterine gland genesis after neonatal CC exposure occurs in conjunction with prolonged luminal epithelium hypertrophy.