The metastatic cascade is a multi-step process and the orthotopic tumor models represent a comprehensive and unique tool for studying metastases compared to experimental intravenous models, which bypass the spontaneous release and dissemination of tumor cells from the primary site to multiple organs. Orthotopic tumor models must recapitulate the progression of cancer and enable the evaluation of both anti-tumor and anti-metastatic activities of therapeutic agents clinical candidates. In the preclinical setting, improved animal models are still needed to mimic the advanced clinical disease and evaluate the anti-metastatic potential of anti-cancer therapies. Most of the experimental animal models utilize serially passaged tumor cell cultures that do not recapitulate the clinical heterogeneity of cancer. Tumor cell xenografts derived from patient specimens (PDCellXs) are more heterogeneous and potentially more predictive of human cancer than those derived from cultured cells lines. Angiogenesis plays a critical role in metastatic colonization along with the non-angiogenic processes of cell adhesion, migration, invasion, and proliferation; both endothelium and tumor cells cooperate in the formation and growth of metastases. The patient derived cell xenografts (PDCellXs) maintain the original patient tumor phenotype, as determined by FACS and histological analysis, and their ability to form metastases in multiple organs. These models enable to evaluate treatments against targets in tumors and vasculature. There are still not fully understood aspects of the metastatic process. Only cells with limitless proliferative potential and innate plasticity have been suggested to survive and successfully establish a metastatic colony. Recently it has been proposed that cancer cells with stem cell-like properties might be responsible for all stages of metastatic cascade; this would explain both the metastatic inefficiency and the clonal origin of metastases. A number of epithelial tumor studies support the evidence that chemotherapy enriches for CSCs that are left behind in the primary tumor after treatment, suggesting that CSCs may be responsible for tumor resistance, recurrence, and metastases.