Lymphangioleiomyomatosis (LAM), a rare multisystem disease affecting women, is characterized by the proliferation of “LAM cells” in the lung (cysts), kidney (angiomyolipomas), and along axial lymphatics (lymphangioleiomyomas).  LAM occurs sporadically or in association with tuberous sclerosis complex (TSC).  LAM lung cells are abnormal smooth muscle-like cells expressing melanoma antigens (e.g., Pmel17/gp100).  LAM cells have a dysfunctional TSC2 or TSC1 tumor suppressor gene, which leads to hyperactivation of the kinase, mammalian Target Of Rapamycin (mTOR).  Some of the factors that contribute to the multisystem manifestations of LAM are known; we have found that circulating LAM cells, which serve as a biomarker, possess pro-metastatic (e.g., CD44v6, CCR10, CXCR4) cell surface molecules.  LAM cell proliferation and migration appear to be modulated by chemokines (e.g., CCL2/MCP-1) and growth factors (e.g., erythropoietin, prolactin).  Although rapamycin (sirolimus) is currently a therapy of choice, defining the molecular and cellular mechanisms of LAM may help in our understanding of disease progression and perhaps lead to novel therapies.