U terine leiomyomas are a major health problem for women of reproductive age. The molecular biology of these tumors is poorly understood partly because of the lack of relevant animal models. We have produced transgenic mice expressing the simian virus 40 T antigen driven by the promoter of the Calbindin-D9K (CaBP9K) gene and either -1,000 or -117 bp of regulatory sequences so as to establish in vivo, uterine smooth muscle tumor models. Six transgenic mouse lines were obtained. Leiomyomas developed in all of them, with an almost complete penetrance of the phenotype. The smooth muscle tumors arose in different parts of the female reproductive tract. Leiomyomas usually developed in the corpus of the uterus, but one mouse line developed leiomyomas in the horn of the uterus, and another in the vagina. The CaBP9K regulatory sequences directing the expression of the Tag gene possess an estradiol responsive element, and accordingly, development of the tumors was strictly under the control of estrogen. Expression of the Tag gene is not only necessary for the initiation of the tumor but also for its development and maintenance. These transgenic mouse models should be useful for studying the pathobiology of uterine leiomyomas and could be instrumental in designing new therapeutic approaches to this disease.