Germline mutations of the LKB1 tumor suppressor gene result in Peutz-Jeghers syndrome (PJS) charac-terized by intestinal hamartomas and increased inci-dence of epithelial cancers. Inactivating mutations in LKB1 have also been found in certain sporadic human cancers and with particularly high frequency in lung cancer. LKB1 has now been demonstrated to play a crucial role in pulmonary tumorigenesis, controlling initiation, differentiation, and metastasis. Recent evi-dences showed that LKB1 is a multitasking kinase, with great potential in orchestrating cell activity. Thus far, LKB1 has been found to play a role in cell polarity, energy metabolism, apoptosis, cell cycle arrest, and cell proliferation, all of which may require the tumor sup-pressor function of this kinase and/or its catalytic activity. This review focuses on remarkable recent find-ings conceing the molecular mechanism by which the LKB1 protein kinase operates as a tumor suppressor and discusses the rational treatment strategies to indi-viduals suffering from PJS and other common dis-orders related to LKB1 signaling.