BACKGROUND AND OBJECTIVES: Cardiovascular disease (CVD) is the largest contributor to all-cause mortality in patients with end stage renal disease (ESRD). Accelerated vascular calcification is a key risk factor for CVD in these patients. The etiology of vascular calcification and the specific role calcium supplementation may play in accelerating calcification have not been fully elucidated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We summarize published data that report on the association between calcium supplementation, vascular calcification, and CVD in patients with and without ESRD. RESULTS: The majority of randomized, controlled trials in patients with ESRD suggest that calcium supplementation--in the form of calcium-based phosphate binders--leads to a progression of vascular calcification. However, studies showing that calcium-based phosphate binders increase cardiovascular mortality are lacking in patients with ESRD. In contrast, one randomized trial in healthy postmenopausal women reported that, compared with those not receiving calcium supplementation, women who take supplements are at an increased risk for cardiovascular events. CONCLUSIONS: Given the potential for harm with calcium supplementation in healthy postmenopausal women and the evidence that calcium-based phosphate binders are associated with adverse intermediate outcomes in patients with ESRD, calcium-either as a phosphate binder or as a supplement--should be prescribed with caution.