The development of drugs to treat breast and other cancers proceeds through phase I dose finding, phase II efficacy, and phase III comparative studies in the metastatic setting, only then asking if metastasis can be prevented in adjuvant trials. Compounds without overt cytotoxic activity, such as those developed to inhibit metastatic colonization, will likely fail to shrink established lesions in the metastatic setting and never be tested in a metastasis prevention scenario where they were preclinically validated. We and others have proposed phase II primary and secondary metastasis prevention studies to address this need. Herein, we have asked whether preclinical metastasis prevention data agrees with the positive adjuvant setting trials. The data are limited but complimentary. We also review fundamental pathways involved in metastasis, including Src, integrins, focal adhesion kinase (FAK), and fibrosis, for their clinical progress to date and potential for metastasis prevention. Issues of inadequate preclinical validation and clinical toxicity profiles are discussed.