Focal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. FAK promotes tumour progression and metastasis through effects on cancer cells and stromal cells of the tumour microenvironment. FAK has both kinase-dependent and kinase-independent functions that control cell movement, invasion, survival, gene expression, and cancer stem cell self-renewal. Small molecule FAK inhibitors decrease tumour growth and metastasis in several preclinical models and have initial clinical activity in patients with limited adverse events. This review discusses FAK signalling effects on both tumour and stromal cell biology that provide rationale and support for future therapeutic opportunities. FAK is a multifunctional regulator of cell signalling within the tumour microenvironment. During development and in various tumours, FAK promotes cell motility, survival, and proliferation through kinase-dependent and kinase-independent mechanisms. In the past few years, Phase I and II clinical trials have been initiated with FAK inhibitors; however, some of the functions of FAK in tumorigenesis remain under investigation. Chromosomal region 8q24.3, which encompasses protein tyrosine kinase 2 (PTK2; which encodes FAK), is linked to susceptibility to ovarian cancer. Large databases such as The Cancer Genome Atlas show that FAK mRNA levels are increased in serous ovarian tumours and invasive breast cancers, and these increased levels are correlated with poor overall patient survival. Increased FAK mRNA levels are also found in several other human malignancies. Studies with tumour tissue arrays find that FAK activation increases with tumour progression. However, unlike classical oncogenes such as RAS or PI3K, only a few missense mutations within PTK2 are found in tumours. Instead, increased FAK activity is associated with PTK2 amplification, and this is consistent with a model whereby increased FAK dimerization that is induced by higher FAK levels contributes to catalytic activation. In this review, we discuss advances in understanding FAK signalling connections in tumour and stromal cells. We cover the intricate roles of FAK in tumour invasion, growth, and metastasis. We highlight genetic mouse models that have been used to elucidate new roles for FAK in endothelial cells and discuss how stromal FAK signalling contributes to tumour progression. Finally, we summarize new translational developments using small molecule FAK inhibitors. FAK regulation involves control of FAK expression, which is regulated by transcription factors such as NF-κB and p53. FAK is also subject to alternative splicing, as PTK2 with deletion of exon 33 results in increased cell motility and invasion. FAK activity is regulated by various mechanisms, including integrin receptor clustering, which promotes FAK activation. FAK is also involved in the regulation of focalFocal adhesion kinase (FAK) is a cytoplasmic protein tyrosine kinase that is overexpressed and activated in several advanced-stage solid cancers. FAK promotes tumour progression and metastasis through effects on cancer cells and stromal cells of the tumour microenvironment. FAK has both kinase-dependent and kinase-independent functions that control cell movement, invasion, survival, gene expression, and cancer stem cell self-renewal. Small molecule FAK inhibitors decrease tumour growth and metastasis in several preclinical models and have initial clinical activity in patients with limited adverse events. This review discusses FAK signalling effects on both tumour and stromal cell biology that provide rationale and support for future therapeutic opportunities. FAK is a multifunctional regulator of cell signalling within the tumour microenvironment. During development and in various tumours, FAK promotes cell motility, survival, and proliferation through kinase-dependent and kinase-independent mechanisms. In the past few years, Phase I and II clinical trials have been initiated with FAK inhibitors; however, some of the functions of FAK in tumorigenesis remain under investigation. Chromosomal region 8q24.3, which encompasses protein tyrosine kinase 2 (PTK2; which encodes FAK), is linked to susceptibility to ovarian cancer. Large databases such as The Cancer Genome Atlas show that FAK mRNA levels are increased in serous ovarian tumours and invasive breast cancers, and these increased levels are correlated with poor overall patient survival. Increased FAK mRNA levels are also found in several other human malignancies. Studies with tumour tissue arrays find that FAK activation increases with tumour progression. However, unlike classical oncogenes such as RAS or PI3K, only a few missense mutations within PTK2 are found in tumours. Instead, increased FAK activity is associated with PTK2 amplification, and this is consistent with a model whereby increased FAK dimerization that is induced by higher FAK levels contributes to catalytic activation. In this review, we discuss advances in understanding FAK signalling connections in tumour and stromal cells. We cover the intricate roles of FAK in tumour invasion, growth, and metastasis. We highlight genetic mouse models that have been used to elucidate new roles for FAK in endothelial cells and discuss how stromal FAK signalling contributes to tumour progression. Finally, we summarize new translational developments using small molecule FAK inhibitors. FAK regulation involves control of FAK expression, which is regulated by transcription factors such as NF-κB and p53. FAK is also subject to alternative splicing, as PTK2 with deletion of exon 33 results in increased cell motility and invasion. FAK activity is regulated by various mechanisms, including integrin receptor clustering, which promotes FAK activation. FAK is also involved in the regulation of focal