It has been shown that glomerular visceral epithelial cells (VEC) proliferate during glomerulogenesis, but differentiated VEC of the fetal kidney do not. It is also recognized that the proliferative capacity of the VEC in mature kidneys is very limited, and according to some investigators, may be completely absent. The basis for this remains unknown. Cell proliferation is controlled by cell cycle-related proteins, of which one class, the cyclin kinase inhibitors (CKI), cause cell cycle arrest and inhibit proliferation. A role for CKI in kidney development is not known. Accordingly, we examined the expression of the CKI p27kip1 (p27) in developing and mature human kidney tissue. Concomitant expression of markers of cell proliferation, Ki-67-related antigen (Ki-67) and proliferating cell nuclear antigen (PCNA), also were examined in fetal and mature human kidney tissue by immunocytochemical techniques. In developing kidney, Ki-67 and PCNA expression are most pronounced in the nephrogenic zone where expression correlates inversely with increasing glomerular maturation. In well-differentiated glomeruli, Ki-67 and PCNA expression is present in some parietal epithelial cells but is absent in the VEC. In contrast, p27 staining exhibits a reverse gradient of expression. p27 is absent in the proliferating tissue exhibiting the earliest stages of differentiation, whereas expression is widespread in the differentiated epithelial cells of more mature glomeruli, in which detectable cell proliferation has ceased. Expression of p27 was not identified in fetal mesangial or glomerular endothelial cells. In the mature human kidney, the pattern of p27 expression identified in differentiated fetal glomeruli persists and appears to be constitutive and specific for glomerular VEC. This pattern of p27 expression in terminally differentiated VEC may explain their limited proliferative capacity in response to injury. This is the first demonstration of a potential role for p27 in human renal development.