Focal segmental glomerulosclerosis (FSGS) is a diagnosis based on the presence of glomeruli with segmental scarring in association with intracapillary foam cells and adhesions. To develop evidence-based treatment guidelines, a MEDLINE search was conducted, and articles were reviewed using levels of evidence. Graded recommendations were developed according to the level of evidence. There was limited evidence found on which to develop recommendations. Treatment with prednisone of 0.5 to 2 mg/kg/day should be considered in all patients and continued for six months before declaring the patient resistant to therapy. Remission is associated with the use of high doses (more than 60 mg/day) for three months; therefore, if there is a concern about prolonged use, a reduction in dose to 0.5 mg/kg/day should be made only after three months (grade D). The use of cyclosporine A (CsA) at doses to maintain serum levels at 150 to 300 microg/ml may be effective in reducing urinary protein excretion. Relapse after reducing or stopping CsA is very common. Long-term use may be required to maintain remission (grade D). The use of cytotoxic therapy (cyclophosphamide, azathioprine, and chlorambucil) for adults is second-line therapy (grade D). Plasmapheresis or protein adsorption may be recommended for renal transplant patients with recurrent FSGS (grade D).