Introduction: About 60% of aplastic anemia (AA) patients are in need of further treatment after frontline standard immunosuppressive therapy (IST). This along with the prolonged survival of AA subjects who do not respond to or relapse after this treatment makes management of these patients a rising and very challenging issue. Areas covered: Literature research, carried out from the most commonly used databases, included the following keywords: aplastic anemia, immunosuppressive treatment, antithymocyte globuline, ciclosporine A, refractory aplastic anemia, relapsing aplastic anemia, hematopoietic stem cell transplantation including haploidentical and cord blood transplantations thrombopoietin mimetics, supportive treatment, chelation and infections. Studies on the treatment of aplastic anemia with different levels of evidence were included. Top level of evidence studies (metanalyses and randomized prospective controlled trials) were a minority because severe AA, particularly in the subset of patients who fail upfront IST, is an extremely rare disease. Guidelines from National Societies and review articles were also included. Expert opinion: The most commonly used treatments after failure of upfront immunosuppression are hematopoietic stem cell transplantation, a second course of immunosuppression and thrombopoietin mimetics alone or in combination with immunosuppression. Other potential options are alemtuzumab, androgens, oral cyclosporine A in monotherapy. Not many comparative studies exist to clearly establish the superiority of one over another strategy. Therefore, the choice of the best treatment for these patients should rely on major driving factors like patient's age and comorbidities, availability of a matched unrelated donor, donor's characteristics and drug-availability.