The techniques of differential protein clearance have been used in the study of patients with renal disease in an attempt to predict the nature of the underlying renal abnormality. Many assumptions that underlie their use are subject to doubt, and differential protein clearances appear to predict the nature of the glomerular disease only in patients with nephrotic syndrome and minimal glomerular changes. When the protein clearance is expressed in terms of the glomerular filtration rate (sieving coefficient), it is a useful index to differentiate the proteinurias associated with glomerular or with tubular damage. This physiologic measure can be used as a valid means of expressing protein handling by normal and diseased kidney.