Thirty to forty percent of patients with idiopathic membranous nephropathy have persistent heavy proteinuria and may progress to end-stage kidney disease in 5 - 15 years. The ideal treatment for these patients is a matter of debate. Several nonspecific immunosuppressive regimens have been suggested with the aim of reducing proteinuria and to improve outcome, but all are burdened by significant toxicity. Therefore, more specific and less toxic therapies are needed. Promising results have been recently obtained with rituximab, a monoclonal antibody against the CD20 antigen of B lymphocytes that is able to deplete these cells and, thus, neoformation of pathogenetic antibodies. Other novel drugs, such as adrenocorticotropic hormone, mycophenolate mofetil and eculizumab have been proposed. This paper reviews the safety/efficacy profile of various agents that have been proposed as therapy for this disease, with particular focus on the latest, more specific and hypothesis-driven approaches.