Tumour metastasis, the movement of tumour cells from a primary site to progressively colonize distant organs, is a major contributor to the deaths of cancer patients. Therapeutic goals are the prevention of an initial metastasis in high-risk patients, shrinkage of established lesions and prevention of additional metastases in patients with limited disease. Instead of being autonomous, tumour cells engage in bidirectional interactions with metastatic microenvironments to alter antitumour immunity, the extracellular milieu, genomic stability, survival signalling, chemotherapeutic resistance and proliferative cycles. Can targeting of these interactions significantly improve patient outcomes? In this Review preclinical research, combination therapies and clinical trial designs are re-examined.