The application of serum creatinine and cystatin C in patients with CKD has been limited to using estimated glomerular filtration rate (eGFR). Criteria for choosing the best GFR estimating equation are 1) accuracy in estimating measured GFR, 2) optimal discrimination of clinical outcomes, and 3) association with CKD risk factors and outcomes similar to that of measured GFR. Notably, these criteria are often not in agreement; and while the last criterion is the most important, it has been widely overlooked. The primary problem with eGFR is that the non-GFR determinants of serum creatinine and cystatin C, as well as their surrogates (age, sex, and race), associate with CKD risk factors and outcomes. This leads to a distorted understanding of CKD, though eGFR based on serum creatinine appears to be less biased than eGFR based on cystatin C. Because of this problem, the use of eGFR should be limited to settings where knowing actual GFR is relevant and eGFR is more informative about GFR than serum creatinine or cystatin C alone. Such settings include staging CKD severity by GFR and dosing medications cleared by glomerular filtration. Alternatively, the diagnosis of CKD, the longitudinal progression of CKD, and prognostic models for CKD are settings where serum creatinine and cystatin C can be better applied and interpreted without eGFR.