Mechanical stimuli such as forces, fluid shear stresses and pressures play a role in the migration of cancer cells through the endothelial monolayer of blood vessels. In the metastatic step of transendothelial migration (entry into the blood vessels), endothelial dissemination and second transendothelial migration (exit from the blood vessels), forces can originate from four main sources: the cancer cells themselves, the endothelial cells and the cells associated with the cancer such as macrophages, neutrophils, platelets and fibroblasts as well as the surrounding extracellular matrix. Mechanical signals and biochemical stimuli may interact synergistically to guide the transmigration of cancer cells through the endothelium. In this chapter, the hypothesis of synergy is tested as the impact of synergistic effects between cancer cells, such as the clustering of cells, is analyzed during transmigration to migrate more effectively, to better oppose immune attacks, and to resist mechanical forces, such as fluid shear stress in vessels. The most important aspects of cancer cell transmigration are the combination of biochemical factors with mechanical factors that can emanate from at least four different sources and the dynamic transition of cancer cells as well as the clustering of cancer cells. Possible perspectives for cancer metastasis and potential targets for tumor-mitigating drugs can be derived from a better understanding of the interplay between the different cell types and their microenvironment, where mechanical signals in particular seem to be at the forefront. The scientists in the field of cancer research can therefore redefine their position and work synergistically by combining mechanical comprehension with biological knowledge. Finally, the interplay of the different parties involved in the transmigration of cancer cells through the endothelium of blood vessels, with emphasis on the interactions between cancer cells and neighboring cells, is dependent not only on the respective biological and mechanical signals, but also on their synergistic interplay, which effectively contributes to the metastasis of cancer cells.