We have analyzed the histotopography of the renal medulla of the rat in terms of cycles and separations. Cycles are pathways by which solute leaving the medulla in an ascending structure (AVR, AHL) is returned to a deeper medullary level. Separations are based on spatial incontiguity and special characteristics of the interstitium and blood supply. The two concepts are complementary: the compartmentalization resulting from separations imparts specificity to the cycles. Structural lateral heterogeneity, consisting in distinct domains organized around vascular bundles, is present in one form or another in all three medullary zones. Such compartmentalization probably leads to heterogeneity in interstitial solute concentrations, a state of affairs inconsistent with the requirements of a "central core". In all such considerations of exchanges between compartments, the lack of a unitary interstitium must be borne in mind. Instead, three general types of interstitium may be distinguished: corresponding roughly to those of the OS and VB, the interbundle region of the IS, and the IM. Among the histotopographic features of the renal medulla not usually included in models of the urinary concentrating mechanism but likely to have functional significance are the association of CD with completely distinct populations of AVR and AHL in the OM and IM; a clear-cut separation throughout the medulla between cycles involving long loops and those involving short loops; the lack of an effective countercurrent association between ascending and descending limbs of short loops in the IS; and a pronounced separation of the venous drainage of the IM from that of the OM.