Only with prospective randomized controlled trials is it possible to evaluate the several immunosuppressive regimens available to renal allograft recipients. Commonly used surrogate markers of clinical outcome, such as patient and graft survival, are constantly improving. Current immunosuppressive protocols have improved 1-yr graft survival to over 90%. The small differences in graft survival among the various immunosuppressive regimes require large patient cohorts in order to establish statistical significance. Such studies are often difficult to conduct in a timely manner, particularly in children. This necessitates the search for better surrogate markers sensitive enough to detect differences in smaller cohorts and in a shorter period of time. While the degree of fibrosis in transplant biopsies might well predict long-term graft survival, protocol biopsies are expensive, invasive, and unpopular among clinicians. In native kidneys, glomerular filtration rate (GFR) closely correlates with disease progression and interstitial fibrosis and appears to be well positioned as a less invasive surrogate marker for long-term outcome. Nonetheless, the ideal marker for GFR remains obscure. Serum creatinine has several major drawbacks, making it a poor predictor of GFR. This review discusses the several methods used to estimate or measure GFR with emphasis on 125I-iothalamate clearance and serum cystatin C (cys-C). Of all the serum markers, cys-C is the most reliable and the most promising. However, cys-C and other endogenous markers cannot replace the diagnostic sensitivity and reliability of radiolabeled markers of GFR such as 125I-iothalamate in renal transplant clinical trials. Unfortunately, clearance of most radiolabeled markers of GFR including 125I-iothalamate remain costly and time consuming.