LKB1 acts as a master kinase, with its major protein targets being the family of AMPKs. Through activation of multiple signaling pathways, LKB1's main physiologic functions involve regulating cellular growth, metabolism, and polarity. Germline mutations in LKB1 result in Peutz-Jeghers Syndrome, a rare cancer susceptibility syndrome. In addition, multiple LKB1 mutations have been identified in sporadic cancers, especially those of the lung. Recent studies from a variety of murine models have helped characterize LKB1's role in the pathogenesis of epithelial cancers. In some tumor types, LKB1 might function chiefly to suppress cell growth or invasion, while in other cases, it may serve to prevent metastasis. Moreover, molecular signatures of individual tumors likely influence LKB1's operational role, as multiple studies have shown that LKB1 can synergize with other tumor suppressors and/or oncogenes to accelerate tumorigenesis. To date, LKB1 has been considered mainly a tumor suppressor; however, some studies have suggested its potential oncogenic role, mainly through the suppression of apoptosis. In short, LKB1 is a tissue and context-specific kinase. This review aims to summarize our current understanding of its role in the pathogenesis of epithelial cancers. © 2011 Elsevier Ireland Ltd.