For metastasis to occur, tumor cells must first detach from their tissue of origin. This requires altering both the tissue of origin and the cancer cell. Once detached, cancer cells in circulation must also acquire survival mechanisms. Although many may successfully disseminate, variation exists in the efficiency with which circulating tumor cells home to and invade the bone marrow as metastastic seeds. Disseminated tumor cells that do successfully invade the marrow are secured by cell-cell and cell-extracellular matrix adhesion. However, establishing a foothold in the marrow is not sufficient for disseminated tumor cells to create metastases. A significant latent phase must be overcome by either rescuing cellular proliferation or attenuating micrometastatic mass dormancy programs. Finally, growing metastases fuel osteolysis, osteoblastogenesis and T-cell differentiation, creating a variety of tumor phenotypes. Each step in the metastatic cascade is rich in biological targets and mechanistic pathways.