The epithelial differentiation of the loop of Henle was investigated in the kidneys of Wistar rats between embryonic day 15 and postnatal day 30. Three stages can be distinguished in the development of the loop of Henle: (1) the primitive loop, (2) the immature loop and (3) the mature loop. The primitive loop of Henle is composed of thick undifferentiated tubule epithelium and is divided into a strongly basophilic proximal tubule anlage that stains dark in the semithin section, and a weakly basophilic, light-staining distal tubule anlage. The two anlages are separated by a cytologically sharp boundary located in the descending limb just before the bend of the loop. The immature loop of Henle is present when differentiation of the tubule epithelium begins. The shorter initial portion of the proximal tubule anlage develops into proximal straight tubule epithelium with brush border, brush border enzymes and lysosomal enzymes, while the longer, more distal portion of the proximal tubule anlage develops into thin undifferentiated epithelium that is a transitory feature of the immature loop stage. The primitive epithelium of the distal tubule anlage develops into distal straight tubule epithelium. The cytologically sharp boundary of the thin undifferentiated epithelium and distal tubule epithelium is located just before the bend of the loop. The loop of Henle matures as the thin undifferentiated epithelium in the medullary ray and outer stripe of the outer medulla becomes transformed into proximal straight tubule epithelium. At the point where this descending differentiation ends, the borderline of the inner and outer stripe of the outer medulla arises. The thin undifferentiated epithelium in the inner stripe and the inner medulla differentiates into the thin epithelium of the descending limb of Henle's loop. In the bend and ascending limb of long loops, the thick distal tubule epithelium is trans-formed by an ascending autophagous process into the thin epithelium of the ascending limb of Henle. The termination of this process marks the borderline between the inner and outer medulla. The thin descending and thin ascending limb of Henle arise from 2 different anlages; between them lies the histogenetic boundary of the proximal and distal renal tubule.