Cells communicate constantly with their surrounding extracellular matrix (ECM) to maintain homeostasis, using both mechanical and chemical signals. In cancer, abnormal signaling leads to stiffening of the ECM. A stiff microenvironment affects many aspects of the cell, including internal molecular signaling as well as behaviors such as motility and proliferation. Thus, cells and ECM interact in a feedback loop to drive matrix deposition and cross-linking, which alter the mechanical properties of the tissue. Stiffer tissue enhances the invasive potential of a tumor and decreases therapeutic efficacy. This chapter describes how specific molecular effects caused by an abnormally stiff tissue drive macroscopic changes that help determine disease outcome. A complete understanding may foster the generation of new cancer therapies.