Background and objective: By reviewing our current understanding of oxidative injury as a cause of focal segmental glomerulosclerosis (FSGS), we hope to advance the use of antioxidants as a promising treatment in addition to the other therapeutic modalities to slow the rate of progression. Methods: Key references from the past concerning oxidative injury and FSGS were analyzed, together with those from a PubMed search of the literature from 1997 to 2007, to form the basis of this commentary. Results: In animal studies in FSGS produced by subtotal nephrectomy or puromycin injections, evidence of oxidant injury provided the rationale for disease reversal with an antioxidant such as high dose vitamin E. Clinical trial in children with FSGS using vitamin E resulted in significant reduction in proteinuria. Other treatment modalities in children with FSGS over the past four decades were reviewed. These consisted of one or more of the following medications: oral prednisone, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and intravenous methylprednisolone with and without cyclophosphamide or cyclosporine. The prognosis with these recent therapeutic interventions improved the outcome of children with FSGS compared to no treatment as advocated earlier. However, when the current regimen of combined treatment was compared with the regimen of prednisone plus cyclophosphamide, there was no difference in Kaplan-Meier kidney survival rate at a mean follow-up of 12 to 16 years. Conclusion: In reviewing current concepts of oxidant injury and other mechanisms of injury in the development of FSGS and the available modalities of treatment, we call into question, whether the cost and side effects of intravenous methylprednisolone is justifiable on the basis of unchanged kidney survival rates with continuing this particular mode of intervention.