Pulmonary lymphangioleiomyomatosis (LAM) is a rare and very complex disease characterized by inflammation and cystic destruction of the patient’s lungs by dedifferentiated smooth muscle-like cells, whose origin remains unclear. It has been proposed that LAM progenitor cells migrate to the lung from extrapulmonary sources although the molecular basis for the regulation of cell migration and survival required for this to occur is largely unknown. Multiple lines of evidence support the conclusion that the uncontrolled activation of the mammalian target of rapamycin complex 1 (mTORC1) is the driver of this disease as a majority of patients display loss of expression and/or function of the tuberous sclerosis complex (TSC), made up of the tumor suppressors TSC1 and TSC2. Additionally, the allosteric inhibitor of mTORC1, rapamycin, reduces growth of angiomyolipomas that have been associated with LAM as well as significantly improving lung function. Unfortunately, due to feedback loops and other resistance mechanisms, as well as the lack of long-term drug tolerance, rapamycin does not cure the disease. These uncertainties clearly underscore the need to continue to define the mechanisms behind disease initiation, progression and maintenance. Using a newly generated genetically engineered mouse model of this disease, our lab is currently focused on studying LAM pathogenesis, from the origin of the cells that give rise to pulmonary lung lesions to the molecular and metabolic requirements for the progression of the disease with the hopes of finding potential biomarkers and more efficacious therapeutic options.