Because metastases are culpable for >90% of cancer-associated mortality, truly efficacious anti-metastatic therapies are desperately needed. (A) Various rationally designed anti-metastatic compounds trigger measurable responses in pre-clinical preventative settings where treatment is initiated prior to the formation of primary tumors or metastases. (B) Unfortunately, however, many agents that display efficacy in preventative pre-clinical models fail to impair metastasis in pre-clinical intervention settings where treatment is initiated only after the formation of small micrometastases (depicted in blue). Because carcinoma patients frequently already harbor significant numbers of disseminated tumor cells at the time of initial disease presentation, the ultimate translational utility of compounds that are unable to alter the behavior of already-formed metastases is likely be quite limited. In contrast, dasatinib, medroxyprogesterone acetate (MPA), miR-31 mimetics, bisphosphonates, denosumab, SD-208, and LY2157299 inhibit the metastatic outgrowth of already-disseminated tumor cells in intervention assays (depicted in gray). (C) In the end, agents that are capable of eliciting the regression of already-established macroscopic metastases may possess the greatest clinical utility. Compounds displaying such efficacy in pre-clinical intervention settings are quite rare, though several examples have been reported – namely, miR-31 mimetics, bisphosphonates, denosumab, SD-208, and LY2157299. In contrast, many other compounds are incapable of altering the behavior of already-established macroscopic metastases (indicated in blue) – including agents that display efficacy against small micrometastases prior to their overt metastatic colonization. Carcinoma cells are depicted in red. Therapeutic agents whose mechanism of action is believed to principally involve the targeting of non-neoplastic stromal cells are presented within the orange boxes. MMP: matrix metalloproteinase; MPA: medroxyprogesterone acetate.