Acquired idiopathic AA is the most typical form of immune-mediated bone marrow failure; the standard treatment of AA for patients who lack a transplant option is immunosuppressive treatment (IST). The standard IST regimen is horse anti-thymocyte globuline (h-ATG) combined with cyclosporine A (CsA), which results in a long term survival around 65-70%. In the past two decades several efforts have been made to improve these results, however results were quite disappointing. Indeed, the addition of a third immunosuppressive agent (micophenolate and sirolimus) on the h-ATG/CsA platform has not resulted in any benefit. Furthermore, the use of anti-lymphocyte agents other than h-ATG (rabbit-ATG, cyclophosphamide, alemtuzumab) has not reproduced the positive outcome seen with standard h-ATG + CsA, irrespective of a more pronounced lymphocyte depletion observed with these alternative compounds. Thus, at least with the strategies tested so far, the strengthening of IST has not led to improved results. More recently, the use of the thrombopoietin mimetic agent eltrombopag has emerged as a possible option to rescue patients failing IST. Nowadays the protection and/or stimulation of residual hematopoietic stem cells by eltrombopag seem an interesting strategy which, once combined with IST, may improve its clinical efficacy. Prospective studies which combine h-ATG and CsA with eltrombopag are currently ongoing in the United States and in Europe, eventually aiming to establish the best non-transplant treatment of AA in the new millennium.