The visceral glomerular epithelium of immature glomeruli from newborn rats was examined in order to determine the sequence of events that occurs during differentiation of foot processes and filtration slits. Four different stages of glomerular development were defined: vesicle, S-shaped body, developing capillary loop, and maturing stages. During the vesicle stage, the precursor cells of the glomerular and tubular epithelium are joined by occluding junctions at their apices. During the S-shaped body stage, the tubular and parietal visceral glomerular epithelium differentiate, and the occluding zonulae remain along the presumptive tubule lumen and Bowman's space, respectively. With the appearance of capillary loops the parietal and tubular junctions maintain this arrangement, but the junctions of the visceral epithelium are seen at various levels along the lateral cell margins, suggesting that they migrate along the lateral cell surfaces from apex to base. Initially, broad epithelial processes cover the entire outer aspect of the developing basement membrane. After junctional migration interdigitation of epithelial processes is seen, and the processes are joined by focal occluding junctions (maculae or fasciae). With more elaborate interdigitation, fewer and fewer intercellular spaces are closed by occluding junctions, the junctions become less and less extensive, and normal slit architecture with foot processes bridged by slit membranes predominate. Colloidal iron staining (i.e., epithelial polyanion) is first detected along the lateral epithelial cell surfaces early in the capillary loop stage and becomes concentrated along their basal cell surfaces facing the basement membrane at about the same time as interdigitation is occurring. Therefore, facing the basement membrane at about the same time as interdigitation is occurring. Therefore, sialoproteins appear on the epithelial cell surfaces prior to the development of foot processes and slits. This finding is in keeping with the assumption that epithelial polyanion may be required for development and maintenance of normal foot process and slit organization. Prior to the development of extensive interdigitation, the differentiating glomerular epithelium bears a number of striking similarities to the nephrotic epithelium: foot processes are broad, reduced in number, and often joined by focal occluding junctions; slit diaphragms are reduced in number and displaced away from the basement membrane; and ladder-like structures occur in the filtration slits. The epithelial changes seen in aminonucleoside nephrosis therefore appear to represent a "dedifferentiation" to a more primitive organization, and the events that occur early in this disease process represent a rerun inreverse of events that occur during normal glomerular development.