The article by Patricia S. Steeg, from the Women's Malignancies Branch at the National Cancer Institute, discusses the challenges and potential of targeting tumor metastasis. Metastasis, the process by which cancer cells spread from the primary site to distant organs, is a major cause of cancer-related deaths. The therapeutic goals are to prevent initial metastasis in high-risk patients, shrink established lesions, and prevent additional metastases in patients with limited disease. Tumor cells interact bidirectionally with the metastatic microenvironment, altering antitumour immunity, extracellular milieu, genomic stability, survival signaling, chemotherapeutic resistance, and proliferative cycles. Preclinical research, combination therapies, and clinical trial designs are re-examined to identify druggable pathways that can enhance the efficacy of current treatments. The review highlights the complexity of metastasis, including the genomic and functional changes that occur during the metastatic process. It discusses the importance of understanding the metastatic cascade, from seeding to dormancy and colonization. Preclinical models, such as spontaneous and experimental metastasis assays, are crucial for developing metastasis-related therapeutics. However, the reproducibility of mouse experiments has been criticized, and the design of preclinical models must be carefully considered to reflect the heterogeneity of human metastases. The article also explores the challenges in treating established metastases, which require cytotoxic agents to kill tumor cells. Two main approaches are under development: immune checkpoint inhibitors and α-particle-emitting radionuclides. The success of these therapies in clinical trials is discussed, along with the need for combination therapies to address the genomic and phenotypic instability of metastatic tumor cells. Finally, the review emphasizes the importance of preclinical experiments and clinical trial designs that are tailored to the prevention or delay of metastasis. Adjuvant trials and alternative trial designs, such as those using high-risk patients or post-treatment metastasis prevention trials, are suggested to better evaluate the effectiveness of antimetastatic therapies.The article by Patricia S. Steeg, from the Women's Malignancies Branch at the National Cancer Institute, discusses the challenges and potential of targeting tumor metastasis. Metastasis, the process by which cancer cells spread from the primary site to distant organs, is a major cause of cancer-related deaths. The therapeutic goals are to prevent initial metastasis in high-risk patients, shrink established lesions, and prevent additional metastases in patients with limited disease. Tumor cells interact bidirectionally with the metastatic microenvironment, altering antitumour immunity, extracellular milieu, genomic stability, survival signaling, chemotherapeutic resistance, and proliferative cycles. Preclinical research, combination therapies, and clinical trial designs are re-examined to identify druggable pathways that can enhance the efficacy of current treatments. The review highlights the complexity of metastasis, including the genomic and functional changes that occur during the metastatic process. It discusses the importance of understanding the metastatic cascade, from seeding to dormancy and colonization. Preclinical models, such as spontaneous and experimental metastasis assays, are crucial for developing metastasis-related therapeutics. However, the reproducibility of mouse experiments has been criticized, and the design of preclinical models must be carefully considered to reflect the heterogeneity of human metastases. The article also explores the challenges in treating established metastases, which require cytotoxic agents to kill tumor cells. Two main approaches are under development: immune checkpoint inhibitors and α-particle-emitting radionuclides. The success of these therapies in clinical trials is discussed, along with the need for combination therapies to address the genomic and phenotypic instability of metastatic tumor cells. Finally, the review emphasizes the importance of preclinical experiments and clinical trial designs that are tailored to the prevention or delay of metastasis. Adjuvant trials and alternative trial designs, such as those using high-risk patients or post-treatment metastasis prevention trials, are suggested to better evaluate the effectiveness of antimetastatic therapies.