Primary focal segmental glomerular sclerosis (FSGS) commonly presents with nephrotic syndrome. Spontaneous remission is rare and persistent nephrotic syndrome is a marker of poor prognosis. For this reason, obtaining remission using drugs with minimal side effects is desirable. The treatment of FSGS, however, represents a challenge. Not only is there a lack of prospective controlled trials, but FSGS is a syndrome of unknown pathophysiology, generally treated with drugs having a mechanism of action that is poorly understood in this setting, the use of which has often drawn criticism because it is based on empirical assumptions rather than pathogenetic evidence. At present, corticosteroids are the standard first-line approach in patients with idiopathic FSGS. Cytotoxic agents and cyclosporin A constitute a good therapeutic option for steroid-dependent patients or frequent relapsers. Mycophenolate mofetil, rituximab and plasmapheresis should be used as rescue treatment because further studies are required to determine their safety and efficacy. Clearly, real progress in FSGS treatment can only be obtained by research focused on the pathophysiology of this disease, so that a therapeutic approach can be defined that is based on reason rather than chance.