The uremic syndrome is a mix of clinical features resulting from multiple organ dysfunctions which develop when kidney failure progresses, and is attributed to the retention of solutes, which under normal conditions are excreted by the healthy kidneys into the urine. The most practical classification of uremic solutes is based on their physicochemical characteristics that influence their dialytic removal, in (1) small water soluble compounds, (2) the larger "middle molecules," and (3) the protein bound compounds. Hence, uremic retention is much more complex than originally believed. Among the small water soluble compounds, urea exerts not much toxic activity and is not very representative in its kinetic behavior for many other uremic solutes. Among the middle molecules, many have been recognized to exert biological activity and hence to contribute to the uremic syndrome. Specific dialysis strategies apply large pore membranes to remove those middle molecules and have a beneficial impact on uremic morbidity and mortality. A substantial number of uremic solutes are protein bound. Only recently, a relation between their concentration and clinical status could be demonstrated. Likewise, it was only recently possible to demonstrate more than standard removal with super-flux dialysis membranes. To further improve characterization of uremic solutes and to develop directed therapeutic approaches, further concerted action among various groups of researchers will be needed.