The formation of distant metastases is the deadliest phase of cancer progression. Although numerous studies have identified genes and mechanisms that affect metastasis after tumors have reached secondary sites, our knowledge about how cancer cells initially gain access to systemic circulation is limited. Since tumors can enter the blood directly by intravasating into venous capillaries or indirectly via lymphatics, it is important to evaluate the relative contributions of both pathways as routes of egress from the primary site. Insights into tumor and stromal factors governing the intravasation process may help explain why certain tumors exhibit “preferred” pathways for metastatic dissemination, both clinically and in experimental animal models.