Without efficient communication, a cell’s ability to survive in a system would be improbable. Moreover, the efficiency with which cancer cells metastasize is attributed to the proficiency with which tumorigenic cells integrate signals from both their surrounding environment and intracellular processes. The mechanosensing ability of a cell is such a process that impacts cellular differentiation, migration, proliferation, and apoptosis. The migratory ability of a cell requires rearrangement of cellular actin scaffolds for the formation of protrusive structures, such as pseudopodia, and secretion of proteolytic enzymes that degrade the extracellular environment. Adhesive structures, such as cadherins and integrins, are tightly regulated processes to efficiently mediate cell migration and apoptosis. In order to properly investigate the behavior of molecular level interactions, scientific research has begun to probe into such dynamic processes at the systems level. This chapter explores the signaling cascades associated with cancer cell migration and those known to be influenced by the mechanical variations of the extracellular matrix.