Besides their contribution to hemostasis and wound healing, platelets and their precursors megakaryocytes have a prominent role in cancer progression to metastatic disease. Several steps of the metastatic cascade are facilitated by the direct interaction of tumor cells with platelets, including adhesion to endothelial cell, evasion from antitumor immunity, recruitment of pro-metastatic immunity, and transendothelial migration, as well as establishment of pre-metastatic niches. Recent evidence has shown that not only tumor cells induce aggregation of platelets and coagulopathies but also “educate” platelets by altering their transcriptomic, proteomic, and metabolic profile, resulting in structural and functional changes. How these tumor-educated platelets affect metastatic dissemination still needs to be determined. Primary tumors also promote the expansion of megakaryocytes at different organ sites, causing paraneoplastic thrombopoiesis. In turn, megakaryocyte-derived cues have been shown to both support and hamper metastatic outgrowth, according to cancer type. The close relationship between platelets and cancer metastasis suggests that anticoagulants might reduce cancer-related coagulopathies and metastasis altogether. We will review the clinical literature on the topic and discuss potential relevance of platelet inhibition in the management of cancer progression and patient survival.