Metastasis is the culmination of numerous highly regulated sequences of steps that results in the proliferation and migration of cells from the primary site to a distant location. The biologic consequence of skeletal metastasis is focal bone sclerosis or osteolysis that leads to pain, pathologic fracture, and biochemical derangement. The difficulty in determining a point of control for clinical application has been because of the numerous systems, substrates, ligands, receptors, factors, and pathways that exist. These may be grouped into functional mechanisms identifiable by their relevance to the metastatic process. These include cell-cell or cell-matrix adhesion, invasion and migration, interactions with endothelial cells, growth factor regulation, proteolysis, and stimulation of differentiated osteoblast and osteoclast function. The challenge for cancer therapy will be to identify means to prevent metastasis or reduce its effect once it occurred. This review examines recent advances in the study of molecular processes of metastasis, which have identified potential sites and substrates for targeting with novel therapies and agents.