Background: Millions of people are affected by irreversible loss of renal function and thus by a significantly increased cardiovascular risk. In this context, the parietal epithelial cells (PECs) of the glomerulus have attracted increasing attention in recent years. So far, they have been ascribed 2 major functions: (1) PECs may act as intrinsic progenitor cells to replenish podocytes and/or proximal tubular cells and (2) a major role of PECs has been proposed in 2 glomerular disease entities [i.e. rapidly progressing glomerulonephritis (RPGN) and focal and segmental glomerulosclerosis (FSGS)]. Summary: In this review, the major recent findings regarding the role of PECs in glomerular disease are summarized. Novel transgenic technologies have allowed major advances, in particular cell fate-tracing studies. Key Messages: Using these methods, it could be established that the proliferating cells in Bowman's space, which are characteristically found in RPGN, are derived almost exclusively from the glomerular epithelium - primarily PECs. Similarly, it could be shown that PECs participate in the formation of sclerotic lesions in FSGS. Since PECs deposit their characteristic extracellular matrix within these lesions, they likely contribute to the sclerotic process. A common feature of both diseases is that PECs are ‘activated', i.e. PECs acquire a larger cytoplasm and nucleus and show increased migration and/or proliferation. Activated PECs can be identified by de novo expression of the marker CD44. These findings broaden our understanding of the pathogenesis of 2 different glomerular diseases: RPGN and FSGS. The participation of activated PECs in both diseases identifies these cells as prime pharmacological targets to develop more specific therapies for both diseases.