The extracellular matrix (ECM) is a master regulator of cellular phenotype and behaviour. It plays a crucial role in both normal tissue homeostasis and complex diseases such as cancer. The interplay between the intrinsic factors of cancer cells themselves, including their genotype and signalling networks; and the extrinsic factors of the tumour stroma, such as the ECM and ECM remodelling; together determine the fate and behaviour of cancer cells. As a consequence, tumour progression, metastatic spread and response to therapy are ultimately controlled by ECM-driven fine-tuning of intracellular kinase signalling. The ability to target and uncouple this interaction presents an emerging and promising potential in the treatment of cancer.