Activated protein C (APC) is best known as a natural anticoagulant that also has direct cell signaling properties which (among others) enhance vascular barrier function. We recently established the relevance of APC-induced barrier enhancement by showing that endogenous APC limits cancer cell extravasation. In line with this concept, repeated administration of exogenous APC reduced the number of experimental metastasis. It is thus tempting to speculate that exogenous APC administration would be a novel therapeutic avenue to fight cancer metastasis. The current review summarizes recent data on the role of the protein C pathway in cancer metastasis. It discusses the APC pathway as a potential novel target to influence cancer progression, but it also points to several limitations of APC administration in the setting of cancer cell metastasis.