Immunodeficient mice are widely used for cancer research as they can provide an in vivo system in which to study the tumorigenicity and metastatic potential of human cancer cells. The athymic or "nude" mouse has been employed for a variety of experimental analyses of tumor growth, invasion, and metastasis. This chapter describes two types of experimental design for studying metastasis in vivo. The spontaneous metastasis models assess the ability of cells to disseminate from a local tumor, and are commonly initiated by the injection of the cells into an organ reflecting the tissue of origin of the cancer (orthotopic injection). Models of experimental metastasis evaluate the ability of tumor cells to arrest, extravasate, and grow in various organs following intravascular injection. The appropriate design of animal models using nude mice, and established human tumor cell lines, assists in the generation of novel information about the metastatic phenotype, and provides a valuable, preclinical system for testing anti-metastatic therapies.