The tumor microenvironment is rich in cell types whose normal function is subverted by malignant cells for tumor development and progression. Platelets are implicated in creating an immunotolerant environment where tumor cells acquire a more aggressive phenotype, create new vasculature, and ultimately invade and metastasize. Platelets play a fundamental role in preparing the pre-metastatic niche for colonization. During metastasis platelets provide a shield for tumor cells against recognition and attack from immune cells and assist in intravasation to the secondary site. This chapter presents the hemostatic and immunomodulatory role of platelets in tumor progression and considers preventive strategies and therapeutic implications.