By definition, animal models provide only an approximation of clinical reality. One reason for this, for example, is that although metastases are the primary cause of mortality from neoplasia, by are rarely considered a target in drug discovery and development. Due to the impact of metastasis on clinical disease, we posit that metastasis should be considered in drug discovery, in addition, to more traditional biologic concepts, including drug pharmacology and toxicity. Drug discovery and developmental studies can incorporate orthotopic and spontaneous metastasis models (syngeneic and xenogeneic) with their inherent host-tumor microenvironmental interactions, in addition to confirmatory autochthonous and/or genetically engineered models (GEMs). This requires a rational and hierarchical approach using models of metastatic disease optimally using resected, orthotopic primary tumors and clinically relevant outcome parameters. In this chapter, we provide protocols for models of metastasis that can be used in translational and drug discovery studies.