The vascular system has a remarkable plasticity as it reshapes continuously in response to changes of the body’s needs. Endothelial cells,  which line the luminal side of all vessels, play a major role in driving the formation, extension and remodeling of blood vessels. These processes heavily rely on cytoskeleton rearrangements that are controlled by soluble factors, matrix proteins, cell-cell interactions and mechanical forces. We have discovered actin-based cytoskeletal structures, called podosomes, in endothelial cells and we explore their involvment in vascular plasticity.  These findings may impact on therapeutic interventions in vascular and regenerative medicine.