Accumulating data suggest that altered connexin expression and gap junctional communication contributes not only to tumorigenesis but also to metastasis. Recent data from our laboratory and that of others has led us to develop a working hypothesis that would explain the role of altered gap junctional communication in breast cancer metastasis to bone. A schematic of our working hypothesis is illustrated in Figure 3. In this model breast cancer cells bind to osteoblastic bone lining cells through cell-cell adhesion molecules (1). Heterotypic gap junctional intercellular communication is established between the breast cancer cells and osteoblastic cells (2). This results in the mobilization of intracellular cytosolic calcium in the osteoblastic cells (3) activating myosin light chain kinase and retraction of the osteoblastic cells away from one another (4). This opens up a pathway that facilitates breast cancer cell migration through the layer of bone lining cells providing access to the bone extracellular matrix. It should be noted that a similar mechanism might explain breast cancer cell transendothelial migration. Future studies will address the four steps in this model and may lead to the development of novel therapeutics targeting connexins and gap junctional communication in breast cancer metastasis.