Vascular calcification is associated with significant cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD). Factors unique to patients with CKD, such as hyperphosphatemia, predispose these patients to early and progressive vascular calcification. Hyperphosphatemia appears to be involved in a number of mechanisms that trigger and advance the progression of vascular calcification, including (1) transition of vascular smooth muscle cells (VSMCs) from a contractile to an osteochondrogenic phenotype and mineralization of VSMC matrix through sodium-dependent phosphate cotransporters, (2) induction of VSMC apoptosis, (3) inhibition of monocyte/macrophage differentiation into osteoclast-like cells, (4) elevation of fibroblast growth factor 23 levels, and (5) decreases in klotho expression. Whether vascular calcification can be prevented or reversed with strategies aimed at maintaining phosphate homeostasis presently is unknown. This review discusses these mechanisms in depth, exploring the interplay among vascular calcification promoters, inhibitors, and substrate that affect phosphorus handling leading to vascular calcification in individuals with CKD.