Human cancer is characterized by a process of tumor cell motility, invasion, and metastasis. One of the critical tyrosine kinases that is linked to these processes of tumor invasion and survival is the Focal Adhesion Kinase (FAK). Our laboratory was the first to isolate FAK from human tumors, and in our initial report, we demonstrated that FAK mRNA was upregulated in invasive and metastatic human breast and colon cancer samples. We identified several binding partners of FAK in cancer cells, such as RIP, VEGFR-3, p53, and IGFR proteins. Recently, we have cloned FAK promoter and have found that FAK promoter contains p53 binding sites, and that p53 inhibits FAK transcription and regulates its expression in tumor samples. In addition, we have found that N-MYCN binds FAK promoter and induces FAK transcription in neuroblastoma cells. Thus, we will review FAK structure and discuss novel proteins and pathways interacting with FAK and discuss the role of FAK-mediated signaling in tumorigenesis (especially in breast, colon, pancreatic, and neuroblastoma cancers). Thus, this review will be focused on FAK signal transduction pathways and FAK-targeted therapy, linking signaling from extracellular matrix to the nucleus in cancer cells. © Springer Science+Business Media, LLC 2010. All rights reserved.