Successful replacement of renal function with dialysis supports the concept that uremia is a toxic state resulting from accumulated solutes and that toxicity results from high concentrations of these solutes in body fluids. Dialyzer clearance of urea, a surrogate toxin, is the currently accepted best measure of dialysis and dialysis adequacy, but it is admittedly a compromise due to current lack of knowledge about and inability to measure more toxic solutes. This failure could be explained if uremic toxicity is actually a summation effect of multiple toxins, each at individual subtoxic levels in the patient. Other solutes could be used as surrogates to measure clearance, but urea happens to be available in high concentrations, is easily measured by all clinical laboratories, and is easily dialyzed, so changes in concentration are sensitive indicators of clearance. Measurements of creatinine clearance are confounded by the disequilibrium that occurs across red cells within the dialyzer and in the patient. Other solutes probably behave more like creatinine than urea, so urea stands out as uniquely diffusible, a property that actually spoils its effectiveness as a surrogate toxin, especially when applied to more frequent and continuous dialysis. Accumulation of other solutes may correlate better with toxic uremic symptoms and the residual syndrome. More studies are needed to examine the kinetics of other solutes, their generation rates, and their distribution volumes to provide clinicians with more knowledge and tools to optimize dialysis treatments. Examination of the effectiveness of solute removal in patients dialyzed more frequently may provide significant insight into the pathogenesis of uremia.