Stk11 (also known as liver kinase b1 (Lkb1)) is a serine-threonine protein kinase that acts upstream of the AMP-activated protein kinase (AMPK) family in coupling energy homeostasis to cell growth, proliferation and survival. Through chondrocyte-specific removal of Lkb1 activity, we showed that Stk11 is required for the normal switch of mitotic chondrocytes to a postmitotic hypertrophic chondrocyte fate. Consequently, it led to a dramatic overgrowth of the growth plate in the Stk11-mutant postnatal skeletal elements. To determine the molecular mechanisms underlying Stk11 action, we examined the mTOR pathway, which is inhibited through AMPK in growth regulation. Strikingly, rapamycin treatment of the pregnant mouse was able to rescue the delay in chondrocyte hypertrophy in Stk11-mutant embryos, suggesting that Stk11 inhibition of mTOR signaling is critical for the switch in chondrocyte fate. Since the dramatic overgrowth of the growth plate is characteristic of enchondroma, we also examined the tumorigenicity of the mutant chondrocytes both in vitro and in vivo . In contrast to wild-type chondrocytes isolated from the postnatal day-30 growth plate, Stk11-mutant chondrocytes proliferated and formed colonies in monolayer and anchorage-independent agar cultures, indicative of a neoplastic transformation in vitro . Similarly, allotransplantation of mutant chondrocytes into immune-deficient NOG mice also resulted in tumor formation in vivo . Gene Ontology analysis of gene expression profiles indicated an augmented activity of cell proliferation and cell cycle regulators within the enchondroma-chondrocyte population compared to chondrocytes in the normal growth plate. Taken together, these data demonstrated an unexpected role of Stk11 in balancing proliferative and nonproliferative hypertrophic states of chondrocyte development through the regulation of mTOR signaling. Stk11 is a known tumor suppressor; our findings raise the possibility that loss of Stk11 may play a role in human enchondroma, a possibility that we are investigating.