Sevelamer is an ion-exchanging resin that binds phosphate in the gut. Because it does so without increasing the calcium load, treatment with sevelamer may lead to less vascular calcification and better survival in chronic kidney disease patients. However, the results of available clinical studies have not been consistent; recent observations challenge the hypothesis that the extra calcium load inherent in calcium-based phosphate binder therapy increases cardiovascular mortality by accelerating vascular calcification. This reemphasizes the fact that we still lack detailed understanding on the complex relationships between vascular calcification, bone metabolism, vascular disease and outcome in the context of uremia. Thus, the role of phosphate binders may be more complex than initially anticipated and not limited to the extra calcium load. Even if detailed mechanisms of action for sevelamer are not yet clearly established (except for its lipid-lowering action), sevelamer may have a number of additional nonphosphate-lowering actions (including lipid lowering as well as improvement in endothelial function, modulation of inflammation and oxidative stress and binding of uremic toxin absorption). Whether these potentially very interesting pleiotropic effects of sevelamer may be translated into significant clinical benefits remains to be established.