Focal segmental glomerulosclerosis (FSGS) is a devastating form of nephrotic syndrome, often leading to end-stage renal failure after the failure of a succession of highly toxic therapies. It has long been thought to be caused by a circulating factor(s) that may be produced by cells of the immune system. Much research has focused on identifying such factor(s), including the development of a promising in vitro assay, which estimates glomerular permeability based on the swelling of isolated glomeruli in response to patients’ plasma. This assay has also been used as the basis of testing plasma fractions for permeability activity, with no specific factor yet identified. Other studies have attempted to replicate proteinuria in whole animals, by injecting plasma or plasma fractions from focal segmental glomerulosclerosis patients, with inconsistent results. More recently there has been evidence that there may be either inhibitory or missing factor(s) in plasma, with respect to permeability. An additional major biological advance is a growing appreciation of the podocyte as the target cell in this disease, and an understanding of the key molecules involved. Putting together this knowledge, with the latest technological advances in protein identification, provides promising avenues towards finally solving the basis of this enigmatic disease.