Uterine leiomyomas, also called fibroids, are the most common reproductive tract neoplasm and the leading indication for hysterectomy in premenopausal women. The discovery and development of medicinal therapies for uterine leiomyoma have been hampered by a lack of understanding regarding the etiology and molecular mechanisms underlying the development of these lesions. Although the estrogen responsiveness of uterine leiomyoma is well established, the impact of environmental estrogens and their contribution to the development of these tumors is currently unknown. The Eker rat model of uterine leiomyoma has proven useful for addressing these issues and understanding the pathophysiology of this disease. The Eker rat is the only animal model that develops spontaneous uterine leiomyomas, and these tumors share many characteristics with those found in humans. The availability of tumor-derived cell lines from these rats has made this a valuable in vitro/in vivo model system for experimental studies to investigate molecular mechanisms of disease and to design interventional and preventative strategies for this clinically relevant tumor.