As has been exemplified by recent progress in the classification of cancer, future approaches to enhance the clinical diagnostic power of tissue biopsies may be based on gene expression profiles. A series of strategies to translate these approaches to the diagnosis of renal disease is here proposed. The theoretical and technical problems resulting from the small amount of starting material available from renal biopsies will be specifically addressed. A preliminary study with cDNA array-based expression data obtained from kidneys with tubulointerstitial inflammation and fibrosis suggests the feasibility of distinguishing molecular categories of renal disease. Finally, a combined conventional and molecular work-up of renal biopsies will be suggested. These approaches should add a new dimension to biopsy interpretation and provide novel information concerning renal pathogenesis, diagnosis, prognosis, and differential therapy. A coordinated effort from nephrologists and pathologists in large multicenter trials will be required to achieve this goal. It is hoped that this outlook will lead to stimulating discussions and the implementation of these innovative ideas in nephrology.