Abstract Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that is highly expressed or activated in many human cancers. Under specific scenarios, FAK can regulate cell proliferation, cell survival, cell migration and invasion, and has been implicated in the control of tumorigenesis and metastasis. FAK has both catalytic and scaffolding activity, and triggers downstream signals by activation of a number of pathways, including the Ras/mitogen-activated protein kinase pathway, the phosphatidylinositol 3'-kinase/Akt pathway, and Rho family GTPases. Recent evidence also suggests novel signaling interactions between FAK and p53. These signaling events were defined primarily from studies on cells in culture, and elucidating which of these signaling pathways are pathologically relevant downstream of FAK in human cancer remains an important goal in determining the molecular mechanisms of tumorigenesis and metastasis. This review discusses select evidence of these signaling pathways with an emphasis on studies linking these to animal models of cancer and human disease. The role of FAK in the process of epithelial-to-mesenchymal transition and in cancer stem cells and recent therapeutic advances targeting FAK are also discussed.