Tumors such as breast, lung, and prostate frequently metastasize to bone, where they can cause intractable pain and increase the risk of fracture in patients. When tumor cells metastasize to bone, they interact with the microenvironment to promote bone destruction primarily through the secretion of osteolytic factors by the tumor cells and the subsequent release of growth factors from the bone. Our recent data suggest that the differential rigidity of the mineralized bone microenvironment relative to that of soft tissue regulates the expression of osteolytic factors by the tumor cells. The concept that matrix rigidity regulates tumor growth is well established in solid breast tumors, where increased rigidity stimulates tumor cell invasion and metastasis. Our studies have indicated that a transforming growth factor-β (TGF-β) and Rho-associated kinase (ROCK)-dependent mechanism is involved in the response of metastatic tumor cells to the rigid mineralized bone matrix. In this review, we will discuss the interactions between ROCK and TGF-β signaling, as well as potential new therapies that target these pathways.