Focal and segmental glomerulosclerosis (FSGS) develops in a number of renal conditions, especially those associated with severe nephrotic syndrome or a reduction in renal mass. Strong evidence suggests that in diseases associated with reduced renal mass that FSGS develops as a consequence of elevated glomerular hydrostatic pressure (P(GC)) resulting from single nephron hyperfiltration. In nephrotic syndrome, the contribution of an elevated P(GC) is less certain. We hypothesize that in both conditions there is an elevation in net ultrafiltration pressure (P(UF)), which in nephrotic syndrome is secondary to a reduction in glomerular plasma oncotic pressure (piGC) and in conditions with reduced renal mass is secondary to an elevated P(GC). The elevated P(UF) would result in increased convective forces with trafficking and deposition of macromolecules in the mesangium, a process that could trigger local cytokine release with the stimulation of cell proliferation and matrix synthesis. In addition to explaining why FSGS develops in both nephrotic syndrome and with reduced renal mass, the hypothesis explains why the lesion in FSGS is segmental and preferentially involves the hilar area. This is because P(UF) varies along the glomerular capillary, being highest at the proximal (afferent arteriolar) end. In contrast, an elevated P(GC) alone does not readily explain the segmental nature of FSGS, because P(GC) remains relatively constant within the glomerulus. Thus, the hypothesis suggests an important role for the plasma oncotic pressure in the pathogenesis of FSGS. Future studies examining the role of P(UF) and piGC in FSGS would be of interest.