Vascular calcification is thought to play a crucial role in the excessive cardiovascular mortality and morbidity in patients with end-stage renal disease (ESRD). Recent evidence suggests that uremic vascular calcification is an active cell-mediated process resembling osteogenesis in bone, rather than passive precipitation of calcium and phosphorus in the setting of deranged mineral metabolism. To date, several bone-associated proteins (osteopontin, bone sialoprotein, alkaline phosphatase, type I collagen) have been demonstrated in histological sections of vessels obtained from patients with ESRD or calcific uremic arteriolopathy. In in vitro experiments, addition of uremic serum upregulates osteopontin expression by cultured vascular smooth muscle cells. We are only beginning to understand the process by which vascular smooth muscle cells transform into osteoblast-like cells, although phosphorus may play a key role. Additional factors mediating or modulating development of vascular calcification in ESRD remain to be identified. Further understanding of the pathophysiology of uremic vascular calcification is needed to design effective therapeutic strategies to intervene with this devastating condition in ESRD population.