Emerging evidences indicate that endothelial progenitor cells (EPCs) actively contribute in regulating cardiovascular homeostasis, and interest is growing for possible future diagnostic and therapeutic applications in the cardiovascular arena. In the present clinically-oriented review, special attention was given to the clinical implications of the potential of EPCs to test and strengthen the capacity of the organism to challenge atherosclerosis, vascular remodelling and ischemia. Accumulating data suggest that the vasculo-protective functions of EPCs may be used as cellular biomarkers for endothelial damage, or may be pharmacologically modulated to enhance the body's defence to atherosclerosis. Furthermore, biomedical engineering and cell transplantation open new scenarios to reverse vascular and graft remodelling and achieve therapeutic angiogenesis in limb and heart ischemia. However, a number of unsolved issues remain to be exploited, such as the identification of the true identity of EPCs and a better characterization of their role in vascular homeostasis under normal and pathologic conditions.