The LKB1 tumor suppressor gene is frequently mutated in sporadic lung adenocarcinomas and cervical cancers and germline mutations are causative for Peutz-Jeghers syndrome characterized by gastrointestinal polyposis. The intracellular LKB1 kinase is implicated in regulating polarity, metabolism, cell differentiation, and proliferation – all functions potentially contributing to tumor suppression. LKB1 acts as an activating kinase of at least 14 kinases mediating LKB1 functions in a complex signaling network with partial overlaps. Regulation of the LKB1 signaling network is highly context dependent, and spatially organized in various cellular compartments. Also the mechanisms by which LKB1 activity suppresses tumorigenesis is context dependent, where recent observations are providing hints on the molecular mechanisms involved.