In the last two decades, our understanding of the genetic underpinnings of inherited podocytopathies has advanced immensely. By sequencing the genomes of a large pool of families affected by focal segmental glomerulosclerosis (FSGS), researchers have identified a common theme: familial podocytopathies are frequently caused by genes selectively expressed in podocytes. Podocalyxin is a podocyte-specific surface sialomucin that has long been known to play important roles in podocyte morphogenesis and function. Few studies, however, have shown a conclusive link between mutations in the gene and FSGS complemented by functional evidence. In a fascinating new paper published in Clinical Science, Lin et al. identify two unrelated pedigrees in which dominant loss-of-function mutations in PODXL lead to adult-onset FSGS. Nonsense-mediated decay of the mutated PODXL transcripts leads to protein insufficiency, which in turn cause podocyte dysfunction through defects in motility and cytoskeletal organization. This is the first study to date that demonstrates, mechanistically, how autosomal dominant mutations in podocalyxin can lead to FSGS and renal insufficiency. Here, we summarize the experimental findings of this manuscript and propose, perhaps, a more controversial hypothesis: down-regulation of podocalyxin protein expression from podocytes is a critical turning point in the progression of most podocytopathies and may be mechanistically relevant to glomerulopathies in which podocyte damage is not necessarily induced by genetic lesions.