In children who exhibit a frequently relapsing course of minimal change disease (MCD), treatment is often difficult and frustrating to the physician and the family since the goal of a sustained remission remains elusive. The progression of the disease is often unpredictable from its clinical presentation since the lesion of MCD may evolve into a more severe form, such as mesangial IgM nephropathy or focal segmental glomerulosclerosis (FSGS), without alteration in signs and symptoms. Alkylating agents such as cyclophosphamide, or immunosuppressives such as cyclosporine can induce a more sustained remission, but are fraught with inherent toxicity, which makes difficult the decision to use these drugs in patients with MCD. Over a 10-year period we studied 49 patients who had more than one renal biopsy. Repeat biopsies were performed either to delineate the morphological lesion prior to change in therapy, or to confirm suspected drug toxicity, which would necessitate discontinuation of therapy. A total of 83 repeat biopsies were performed in these 49 patients. Of the 49 patients, 25 had MCD, and in 21 of these the lesion evolved into either IgM nephropathy (n = 7) or FSGS (n = 14). Of patients with IgM nephropathy (n = 12), 50% evolved into FSGS. The clinical diagnosis made prior to the repeat biopsy did not confirm with the histological diagnosis in 43% of cases, and a change in therapy or cessation of therapy was carried out in 43 of 83 repeat biopsy instances. Since the complications were mild and the ability of clinical findings to accurately predict the histological lesion limited, we conclude that repeat renal biopsies are a useful tool to fashion optimal therapy in children with frequently relapsing nephrotic syndrome.