Focal segmental glomerulosclerosis (FSGS) has been previously characterized as having primary (idiopathic), secondary and familial forms. In the latter category, both autosomal recessive and dominant inheritance patterns have been reported. Reports of familial forms of FSGS date back as far as 1956, with the observation of an autosomal recessive disease primarily within the Finnish population. The disease process is characterized by massive proteinuria in utero, with up to 20 to 30 grams of protein loss per day. NPHS1 encodes a gene product termed ‘nephrin’, within which numerous mutations including deletions, insertions, nonsense, missense and splicing errors have been described. Nephrin localizes to lipid ‘rafts’ within the slit diaphragm of the podocyte. Steroid-resistant nephrotic syndrome (SRNS) is another human disorder that is characterized by autosomal recessive nephrotic syndrome. This disorder manifests between 3 months and 5 years of age, rapid progression to ESRD, and with few cases of recurrence after renal transplantation. The gene product is podocin (NPHS2), located on 1q25-31. Podocin most likely functions in the structural organization of the slit diaphragm and regulation of its filtration function. It has been shown to interact in vivo with both nephrin and CD2-associated protein (CD2AP), a cytoplasmic binding partner of nephrin. Mutations in the alpha-actinin 4 gene (ACTN4), which localizes to chromosome 19q13, have been associated with autosomal dominant FSGS, characterized by adult onset disease of variable severity and rate of progression to ESRD. Fractions of the mutant protein have been shown to form large aggregates within podocytes ultimately compromising the function of the normal actin cytoskeleton, both through its abnormal function and toxic accumulation. Recently, a disease-causing mutation for hereditary FSGS has been localized to chromosome 11q 21-22, with the subsequent identification of transient receptor potential cation channel, subfamily C, member 6 (TRPC6) as the disease causing gene. The missense mutation causes a highly conserved proline in the first ankyrin repeat of TRPC6 to become a glutamine at position 112 (P112Q). Additional work as reported by Reiser et al. has corroborated findings implicating TRPC6 in the pathogenesis of familial FSGS. The TRPC6^P112Q mutation is highly conserved and causes increased and prolonged calcium transients in transfected cells. The mutant channel also significantly enhances cation signals triggered by AT1 receptor activation. Biotinylation and immunostaining studies reveal that the mutation also appears to cause mislocalization of the ion channel to the cell surface. TRPC6–related FSGS suggests an additional mechanism for renal disease pathogenesis. Knowledge of TRPC6-mediated calcium entry into cells may offer unique insights into therapeutic options for glomerular diseases. Calcium as a second messenger affects many cellular functions such as contraction, apoptosis, vasoregulation and mechanosensation to name a few. We suggest that the exaggerated calcium signalling conferred by the TRPC6^P112Q mutation disrupts glomerular cell function or may cause apoptosis. We further speculate that the mutant protein may amplify injurious signals triggered by ligands such as angiotensin II that promote kidney injury and proteinuria. Clinical manifestations of renal disease do not appear until the 3rd decade in individuals with the TRPC6^P112Q mutation. This is in contrast to individuals with Finnish nephropathy and steroid-resistant nephrotic syndrome who typically develop proteinuria in utero or at birth. This delay may reflect the difference between these recessive disorders and the autosomal dominant mechanism of inheritance in our family, as such the presence of one normal TRPC6 allele may postpone the onset of kidney injury. Patients with autosomal dominant FSGS due to mutations in the ACTN4 gene also have a delayed onset of kidney disease. Because channels tend to be amenable to pharmacological manipulation, our study raises the possibility that TRPC6 may be a useful therapeutic target in chronic kidney disease.