Immune mediated destruction of hematopoietic stem/progenitor cells (HSPCs) plays a central role in the pathophysiology of acquired aplastic anemia (aAA). Dysregulated CD8+ cytotoxic T cells, CD4+ T cells including Th1, Th2, regulatory T cells and Th17 cells, natural killer (NK) cells and NKT cells, along with the abnormal production of cytokines including interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α) and tumor growth factor-beta (TGF-β), induce apoptosis of HSPCs, constituting a consistent and defining feature of severe aAA. Alterations in the polymorphisms of TGF-β, IFN-γ and TNF-α gene, as well as certain human leukocyte antigen (HLA) alleles may account for the propensity to immune mediated killing of HSPCs and/or ineffective hematopoiesis. Although the inciting autoantigens remain elusive, autoantibodies are often detected in the serum. In addition, recent studies provide genetic and molecular evidence that intrinsic and/or secondary deficits in HSPCs and bone marrow mesenchymal stem cells may underlie the development of bone marrow failure. This article is protected by copyright. All rights reserved.