We used a phage expression library of cDNAs from metastatic breast carcinoma to identify protein domains that bind to the vasculature of the lung, a frequent site of breast cancer metastasis. We found that one protein domain selectively targeted phage as well as cells to the lung. This domain is part of the protein metadherin, shown by gene expression profiling to be overexpressed in metastatic breast cancer. Immunostaining revealed that metadherin is overexpressed in breast cancer tissue and breast tumor xenografts. Antibodies reactive to the lung-homing domain of metadherin and siRNA-mediated knockdown of metadherin expression in breast cancer cells inhibited experimental lung metastasis, indicating that tumor cell metadherin mediates localization at the metastatic site.