Discovering metastasis genes that are clinically relevant and functionally important are critical for the development of novel therapeutics for high-risk breast cancer patients. Application of genomic profiling technology in animal models of cancer metastasis has allowed the discovery of genes that collectively promote metastasis of breast cancer to bone, lung and other target organs. However, much work remains to be done to validate the clinical relevance of metastasis genes identified in animal model studies. As a second approach, gene expression profiling of human tumor specimens has enabled the identification of several poor-prognosis signatures that are predictive of recurrence and metastasis risk in human cancers. However, the lack of overlap between different poor prognosis signatures raised questions about the biological significance of genes in the signatures and hinders the identification and therapeutic targeting of functionally important metastasis genes. We have developed integrative genomics strategies to bridge clinical and experimental metastasis research. Using such an approach, we recently identified a recurrent 8q22 genomic gain in poor-prognosis human breast cancers, which harbors metastasis gene Metadherin (MTDH). Functional characterization of MTDH in animal models and in vitro functional assays revealed its dual functions in promoting metastasis and broad-spectrum chemoresistance of breast cancers. Together, these results illustrate an integrative strategy to uncover metastasis genes with important prognostic as well as therapeutic values, and establish MTDH as a major target for the prevention and treatment of chemoresistant metastasis.