Cancer metastasis requires a series of sequential steps, each of which is rate limiting. Neoplasms are biologically heterogeneous, and the process of metastasis is highly selective. Multiple metastases often differ in biologic characteristics and can change during the course of the disease. Clonal analysis of human melanoma suggest that systemic, physiologic signals can be recognized by neoplastic cells. Brain metastases are particularly common in patients with metastatic melanoma. The blood brain barrier does not prevent the invasion of the brain parenchyma by circulating metastatic cells, and its permeability varies among different experimental brain metastases.