Uremic retention solutes, if biologically or biochemically active, are called ''uremic toxins''. The retention of these solutes has a negative impact on many functions of the organism, particularly the cardiovascular system. The classification which is applied today is based on the kinetic behavior of the uremic retention solutes during dialysis: 1) small water-soluble molecules ( 500 Daltons); 3) protein-bound compounds. The latter are the object of the present review. The most important among them are p-cresol, p-cresyl sulfate, homocysteine, phenols, and indoles. No interventional studies are currently available that show the effect of an improvement in the removal of protein-bound compounds on patient outcomes, simply because most of the alternative dialysis strategies proposed so far are not superior to standard dialysis in removing protein-bound compounds. The question as to how to improve the removal of these solutes therefore remains unanswered. Alternative strategies might include adsorption therapies, either administered orally or during the extracorporeal treatment. In conclusion, the uremic syndrome is a complex clinical entity which involves a large number of retention solutes, many more than the small water-soluble molecules. Dialysis strategies should therefore aim to remove not only urea but also retention solutes, mainly because middle and protein-bound molecules appear to be correlated more frequently with deleterious biological, biochemical and clinical effects.