Focal segmental glomerulosclerosis (FSGS), a subtype of "idiopathic nephrotic syndrome", is not a single disease, but a lesion that initially affects the glomerulus followed by the tubulointerstitium and renal vessels. The term 'FSGS' does not accurately encompass the various pathologic features of the glomerulus, which are not always focal, segmental or sclerotic. Particular variants of FSGS, such as collapsing glomerulopathy and the glomerular tip lesion, exemplify the nosologic uncertainty inherent in the classification of glomerular lesions. Pathologic variation notwithstanding, all pathologic processes that affect the podocyte lead to one of the histologic subtypes of FSGS. This specialized cell type has essential roles in maintaining the integrity of glomerular architecture, resisting endocapillary hydraulic pressure and hindering egress of proteins into the urinary space. Once initiated, podocyte lesions and ensuing fibrosis are usually irreversible, at least in human forms of FSGS. Remarkable progress has been made in unraveling the mechanisms of podocyte dysregulation that accompany the cellular variants of FSGS and in identifying genetic mutations affecting proteins of the slit diaphragm. Hopefully, this progress will drastically improve treatments for what is one of the most difficult therapeutic challenges to confront the nephrologist.