Lymphangioleiomyomatosis (LAM) is a rare disease characterized by proliferation of abnormal smooth muscle (SM) cells in the lungs. With time, LAM cells proliferate and lead to progressive loss of lung function. No effective treatment for this life-threatening disease is available, and patients often require lung transplantation. LAM has two unique characteristics: 1) LAM demonstrates strong gender specificity, affecting almost exclusively reproductive-age women; and 2) LAM cells contain mutations in genes (TSC1 or TSC2) that encode the tuberous sclerosis complex, a signaling module that limits mTOR activity and thereby cell growth. The origin of LAM cells is not known; however, data support a metastatic model of LAM pathogenesis. Interestingly, LAM shares many features with uterine leiomyomas, the leading reason for hysterectomy among women. Like LAM, leiomyomas are characterized by abnormal SM cell proliferation and are most prevalent during reproductive years. Furthermore, both LAM and leiomyomas express steroid hormone receptors and respond to estrogen and possibly progesterone. We propose that mutations in TSC2, in addition to estrogen and/or progesterone stimuli, trigger myometrial cells to proliferate and metastasize to the lungs similar to LAM cells. To test our hypothesis, we generated a mouse strain with a uterine-specific loss of TSC2. We show that TSC2 expression is low and mTOR signaling elevated in the uteri of post-pubertal uterine-specific TSC2 knockout (KO) mice. Notably, uteri from TSC2 KO mice develop leiomyomas at 5-6 months of age, and these tumors are prevented by treatment with the mTOR inhibitor rapamycin. Furthermore, these myometrial tumors express high levels of estrogen- and progesterone receptors, and uterine growth can be prevented by eliminating ovarian steroid production through ovariectomy. Importantly, multiple lung lesions were seen in a 34-week old TSC2 KO female. These lung tumors express progesterone receptors and are negative for the lung marker, Nkx2.1, indicating that they might be LAM cells. Together, our studies suggest that LAM may indeed originate from uterine myometrial cells. We hope that our model will improve our understanding of both LAM and leiomyomas, and may lead to the development of novel innovative therapeutic strategies for both tumors. Copyright 2012 by The Society for the Study of Reproduction. Copyright 2012 by The Society for the Study of Reproduction.